Heterocyclic compounds, their production and use

ABSTRACT

Heterocyclic compounds represented by the general formula (I)                    
     wherein R stands for an optionally substituted aromatic heterocyclic group; 
     X stands for oxygen atom, an optionally oxidated sulfur atom, —C(═O)— or —CH(OH)—; 
     Y stands for CH or N; 
     m denotes an integer of 0 to 10: 
     n denotes an integer of 1 to 5: 
     cyclic group                    
      stands for an optionally substituted aromatic azole group; and 
     ring A is optionally further substituted, 
     or salts thereof. The compound (I) possesses action of inhibiting tyrosine kinase and useful as antitumor agents.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound useful as thegrowth factor receptor tyrosine kinase (especially HER2) inhibitingagent, a method of producing the compound, and a medicinal compositioncomprising the compound.

BACKGROUND ART

Genes of cell growth factor and growth factor receptors are calledproto-oncogene and play important roles in behavior of human tumorsincluding breast cancer (Arronson et al., Science Vol.254, pp.1141-1153,1991). HER2 (Human EGF Receptor-2 genes having homology with thereceptor of epidermal growth factor EGF are those of transmembranereceptor glycoprotein, and this receptor has tyrosine kinase activity(Akiyama et al., Science Vol.232, pp.1644-1656, 1986). HER2 is observedin human breast cancer and ovarian cancer (Slamon et al., Science,Vol.244, pp.707-712, 1989), which is further observed in prostate cancer(Lyne et al., Proceedings of American Association for Cancer ResearchVol.37, p.243, 1996) or gastric cancer (Yonemura et al., Cancer ResearchVol.51, p.1034, 1991). Further, the substrate of HER2-tyrosine kinase isobserved in 90% of pancreatic cancers. Transgenic mice carrying HER2gene develop mammary cancers as they grow (Guy et al., Proceedings ofNational Academy of Science U.S.A., Vol.89, pp.10578-10582, 1992).

It is disclosed that antibodies specific for HER2 suppress in vitroproliferation of tumor cells (Mckenzie et al. Oncogene Vol.4,pp.543-548, 1989) and humanized monoclonal antibody demonstratedprospective results in the clinical tests of patients suffering frombreast cancer (Baselga et al., Journal of Clinical Oncology, Vol.14,pp.737-747, 1996).

These antibodies hinder the binding of growth factor with HER2 receptorand inhibit activation of tyrosine kinase. As the result, since it wasshown that the advance of breast cancer was suppressed, it was shownthat the drug directly inhibiting tyrosine kinase of HER2 was possiblyeffective as a medicine for the therapy of breast cancer (Hayes, Journalof Clinical Oncology, Vol.14, pp.697-699, 1996).

While several low molecular weight compounds inhibiting receptor-typetyrosine kinase containing HER2 have been reported, most of them arestyrene-like compounds analogous to tyrosine itself having hydroxylatedaromatic ring. For example, erbstatin inhibits proliferation of humanepidermal carcinoma cell line A431 (Journal of Antibiotics, Vol.39,p.170, 1986), and it is reported that tyrphostin has antitumor activityin vivoon nude mice bearing the well-characterized human squamous cellcarcinoma MH-85 (Cancer Research, Vol.51, p.4430, 1991). And, it itreported that sulfonylbenzoyl-nitrostyrene derivatives have antitumoractivities in vivo in nude mice carrying A431 cell line. Further, it hasbeen known that indole derivatives inhibit EGF receptor type tyrosinekinase and inhibit in vivo the growth of A431 cell line (InternationalApplication No. PCT/US93/7272, Japanese Patent Application under PCTlaid-open under Kohyo No.Toku-Hyo-Hei 8-503450).

And, it has been known that triazole and diazole derivatives, althoughthey are not tyrosine kinase inhibiting compounds, have the activity ofinhibiting the signal transduction of cell proliferation due to growthfactor (U.S. Pat. No. 5,482,954).

DISCLOSURE OF INVENTION

The object of this invention is to provide a compound having an actionof inhibiting tyrosine kinase, being useful as an antitumor agent withless toxicity.

The present inventors conducted various studies on heterocycliccompounds having a tyrosine kinase inhibiting action, and, as a result,they synthesized, for the first time, a heterocyclic compoundrepresented by the general formula (I) having a terminal aromatic azolegroup,

wherein R stands for an optionally substituted aromatic heterocyclicgroup;

X stands for oxygen atom, an optionally oxidized sulfur atom, —C(═O)— or—CH(OH)—;

Y stands for CH or N;

m denotes an integer of 0 to 10;

n denotes an integer of 1 to 5; and

the cyclic group

 stands for an optionally substituted aromatic azole group, and the ringA may optionally further be substituted (hereinafter simply called“compound (I)”), or a salt thereof, and found that this compound (I) ora salt thereof has, unexpectedly, an excellent suppressing action oftyrosine kinase based on the specific chemical structure. Based on thisfinding, the present invention has been accomplished.

More specifically, the present invention is to provide

(1) the heterocyclic compound (I) or a salt thereof;

(2) a medicinal composition comprising the heterocyclic compound (I) ora pharmaceutically acceptable salt thereof;

(3) use of the heterocyclic compound (I) or a pharmaceuticallyacceptable salt thereof, for a preparation of a medicinal agent forprophylaxis or treatment for cancer;

(4) a method comprising administering an effective amount of theheterocyclic compound (I) or a pharmaceutically acceptable salt thereofin a pharmaceutically acceptable carrier to provide a prophylactic ortherapeutic action for cancer; and

(5) a method of producing the heterocyclic compound (I) or a saltthereof.

In the present specification, as the heterocyclic group in theoptionally substituted aromatic heterocyclic group shown by R, mentionis made of, for example, (1) a 5- or 6-membered aromatic monocyclicheterocyclic group containing as the ring-forming atoms, besides carbonatoms, 1 to 4 atoms selected from nitrogen atom, oxygen atom and sulfuratom, and (2) an aromatic condensed heterocyclic group formed bycondensation of (i) a 5- or 6-membered aromatic monocyclic heterocyclicgroup containing, as the ring-forming atoms, besides carbon atoms, 1 to4 atoms selected from nitrogen atom, oxygen atom and sulfur atom with(ii) a 5- or 6-membered aromatic or non-aromatic heterocyclic groupcontaining, as the ring-forming atoms, besides carbon atoms, 1 to 2nitrogen atoms, benzene ring or a 5-membered aromatic or non-aromaticheterocyclic group containing, as the ring-forming atoms, besides carbonatoms, one sulfur atom.

Specific examples of these aromatic heterocyclic groups include pyridyl(e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl,4-pyridazinyl), pyrazinyl (e.g. 2-pyrazinyl), pyrrolyl (e.g. 1-pyrrolyl,2-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),isoxazolyl, isothiazolyl, thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl,5-thiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),oxadiazolyl (e.g. 1,2,4-oxadiazolyl such as 1,2,4-oxadiazol-5-yl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g.1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl(e.g. 1,2,4-triazolyl such as 1,2,4-triazol-1-yl, 1,2,4-triazol-5-yl,1,2,4-triazolyl such as 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl),benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl), indolyl(e.g. indol-1-yl, indol-3-yl), indazolyl (e.g. 1H-indazol-1-yl,1H-indazol-3-yl), pyrrolopyrazinyl (e.g. 1H-pyrrolo[2,3-b]pyrazinyl),pyrrolopyridyl (e.g. 1H-pyrrolo[2,3-b]pyridyl), imidazopyridyl (e.g.1H-imidazo[4,5-b]pyridyl, 1H-imidazo[4,5-c]pyridyl, imidazopyrazinyl(e.g. 1H-imidazo[4,5-bpyrazinyl), pyrrolopyridazinyl (e.g.pyrrolo[1,2-b]pyridazinyl), pyrazolpyridyl (e.g.pyrazolo[1,5-a]pyridyl), imidazopyridyl (e.g. imidazo[1,2-a]pyridyl,imidazo[1,5-a]pyridyl), imidazopyridazinyl (e.g.imidazo[1,2-b]pyridazinyl), imidazopyrimidinyl (e.g.imidazo[1,2-a]pyrimidinyl), furyl, thienyl, benzofuranyl, benzothienyl(e.g. benzo[b]thienyl), benzoxazolyl, benzthiazolyl, quinolyl,isoquinolyl and quinazolinyl. Preferable examples include a 5-memberedcyclic aromatic azole group such as oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl, anaromatic condensed azole group formed by condensation with a benzenering such as benzoxazolyl and benzthiazolyl, and a 6-membered monocyclicaromatic heterocyclic group such as pyridyl and pyrimidyl. Furtherpreferable examples of the aromatic heterocyclic group include a5-membered monocyclic aromatic azole group such as oxazolyl group andthiazolyl group.

As the aromatic azole group in the optionally substituted aromatic azolegroup shown by the cyclic group:

mention is made of, for example, (1) a 5-membered aromatic monocyclicheterocyclic group containing, as the ring-forming atoms, besides carbonatoms, 1 to 4 nitrogen atoms and optionally containing one oxygen atomor one sulfur atom, and (2) an aromatic condensed heterocyclic groupformed by condensation of (i) a 5-membered aromatic monocyclicheterocyclic group containing, as the ring forming atoms, besides carbonatoms, 1 to 4 nitrogen atoms and optionally containing one nitrogen atomor one sulfur atom, with (ii) a 5- or 6-membered aromatic ornon-aromatic heterocyclic group containing, as the ring-forming atoms,besides carbon atoms, one or two nitrogen atoms, benzene ring or a5-membered aromatic or non-aromatic heterocyclic group containing, asthe ring-forming atoms, besides carbon atoms, one sulfur atom.

Specific example of the aromatic azole group include aromaticheterocyclic groups such as pyrrolyl (e.g. 1-pyrrolyl), imidazolyl (e.g.1-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl), triazolyl (e.g.1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl), tetrazolyl (e.g.tetrazol-1-yl), benzimidazolyl (e.g. benzimidazol-1-yl), indolyl (e.g.indol-1-yl), indazolyl (e.g. 1H-indazol-1-yl), pyrrolopyrazinyl (e.g.1H-pyrrolo[2,3-b]pyrazin-1-yl), pyrrolopyridyl (e.g.1H-pyrrolo[2,3-b]pyridin-1-yl), imidazopyridyl (e.g.1H-imidazo[4,5-b]pyridin-1-yl), and imidazopyrazinyl (e.g.1H-imidazo[4,5-b]pyrazin-1-yl). These groups are bonded to —(CH₂)_(m)—through the nitrogen atom contained as one of the ring-forming atoms.Preferable examples of the aromatic azole group include imidazolyl groupand triazolyl group.

The aromatic heterocyclic group shown by R and the aromatic azole groupshown by the formula:

may optionally have 1 to 3 (preferably one or two) substituents at anysubstitutable position. Examples of the substituents include aliphatichydrocarbon groups, alicyclic hydrocarbon groups, aromatic hydrocarbongroups, an aliphatic hydrocarbon group substituted with an aromatichydrocarbon group, an aliphatic hydrocarbon group substituted with analicyclic hydrocarbon group, aromatic heterocyclic groups, non-aromaticheterocyclic groups, an aliphatic hydrocarbon group substituted with anaromatic heterocyclic group, halogen atom, nitro group, cyano group, anoptionally substituted amino group, an optionally substituted acylgroup, an optionally substituted hydroxyl group, an optionallysubstituted thiol group, and an optionally esterified or amidatedcarboxyl group. The aliphatic hydrocarbon group, alicyclic hydrocarbongroup, aromatic hydrocarbon group, aliphatic hydrocarbon groupsubstituted with an aromatic hydrocarbon group, aliphatic hydrocarbongroup substituted with an aliphatic hydrocarbon group, aromaticheterocyclic group, non-aromatic heterocyclic group and aliphatichydrocarbon group substituted with an aromatic heterocyclic group mayfurther be optionally substituted, respectively.

The ring A may optionally have, besides X and (CH₂)_(m), 1 to 4(preferably one or two) substituents at any substitutable position. Asthe substituents, mention is made of those exemplified as substituentswhich the substituents on the aromatic heterocyclic groups shown by Rmay optionally have, as exemplified by aliphatic hydrocarbon groups,alicyclic hydrocarbon groups, aromatic hydrocarbon groups, an aliphatichydrocarbon group substituted with an aromatic hydrocarbon group, analiphatic hydrocarbon group substituted with an alicyclic hydrocarbongroup, aromatic heterocyclic groups, an aliphatic hydrocarbon groupsubstituted with an aromatic heterocyclic group, halogen atom, nitrogroup, cyano group, an optionally substituted amino group, an optionallysubstituted acyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, and an optionally esterified oramidated carboxyl group. The aliphatic hydrocarbon group, alicyclichydrocarbon group, aromatic hydrocarbon group, aliphatic hydrocarbongroup substituted with an aromatic hydrocarbon group, aliphatichydrocarbon group substituted with an alicyclic hydrocarbon group,aromatic heterocyclic group, non-aromatic heterocyclic group andaliphatic hydrocarbon group substituted with an aromatic heterocyclicgroup mentioned above as substituents may optionally be furthersubstituted.

As the aliphatic hydrocarbon groups, mention is made of straight-chainor branched aliphatic hydrocarbon groups having 1 to 15 carbon atoms,for example, alkyl group, alkenyl group and alkynyl group.

Preferable examples of the alkyl group include C₁₋₁₀ alkyl groups suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl,tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl,isohexyl, heptyl, octyl, nonyl, decyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, more preferablyC₁₋₆ alkyl groups.

Preferable examples of the alkenyl group include C₂₋₁₀ alkenyl groupssuch as vinyl (ethenyl), allyl, isopropenyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and5-hexenyl, more preferably C₂₋₆ alkenyl groups.

Preferable examples of the alkynyl group include C₂₋₁₀ alkynyl groupssuch as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, more preferably C₂₋₆alkynyl groups.

Examples of the alicyclic hydrocarbon group include C₃₋₁₂ saturated orunsaturated alicyclic hydrocarbon groups such as cycloalkyl group,cycloalkenyl group, cycloalkadienyl group or partially unsaturatedcondensed dicyclic hydrocarbon group.

Preferable examples of the cycloalkyl group include C₃₋₁₀ cycloalkylgroups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl; and C₆₋₁₀ bicycloalkyl groups such asbicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl andbicyclo[4.3.1]decyl.

Preferable examples of the cycloalkenyl group include C₅₋₁₀ cycloalkenylgroups such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yland 3-cyclohexen-1-yl.

Preferable examples of the cycloalkadienyl group include C₅₋₁₀cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl.

Preferable examples of the partially unsaturated condensed dicyclichydrocarbon group include C₉₋₁₂ groups formed by condensation of abenzene ring such as indanyl group or partially unsaturated naphthylgroup (e.g. dihydronaphthyl group such as 3,4-dihydro-2-naphthyl; andtetrahydronaphthyl such as 1,2,3,4-tetrahydronaphthyl) with alicyclichydrocarbon.

As the aromatic hydrocarbon group, mention is made of a monocyclic or acondensed polycyclic aromatic hydrocarbon group, preferably exemplifiedby C₆₋₁₄ aryl groups such as phenyl, naphthyl, anthryl, phenanthrylacenaphthylenyl and 9-fluorenone-2-yl. Among them, monocyclic orcondensed dicyclic aromatic hydrocarbon groups such as phenyl,1-naphthyl and 2-naphthyl are preferable.

As the aliphatic hydrocarbon group substituted with an aromatichydrocarbon group, mention is made of, for example, aliphatichydrocarbon groups substituted with 1 to 3 (preferably 1 or 2) C₇₋₂₀aromatic hydrocarbon groups. Preferable examples of such aliphatichydrocarbon group substituted with an aromatic hydrocarbon group asabove include C₁₋₆ alkyl group substituted with 1 to 3 C₆₋₁₄ aryl groups(e.g. C₁₋₆ alkyl group substituted with 1 to 3 phenyl groups such asbenzyl, 2-phenylethyl, 1,2-diphenylethyl and 2,2-diphenylethyl) and C₂₋₆alkenyl groups substituted with 1 to 3 C₆₋₁₄ aryl groups (e.g. C₂₋₆alkenyl groups substituted 1 to 3 phenyl groups, such as(E)-2-phenylethenyl, (Z)-2-phenylethenyl, 2,2-diphenylethenyl,2-(2-napthyl)ethenyl and 4-phenyl-1,3-butadienyl, and C₂₋₆ alkenylgroups or 9-fluorenyl-C₁₋₆ alkyl group substituted with 1 to 3 napthylgroups).

As the aliphatic hydrocarbon group substituted with an alicyclichydrocarbon group, mention is made of the above-mentioned aliphatichydrocarbon groups substituted with the above-mentioned alicyclichydrocarbon groups.

Preferable examples of such aliphatic hydrocarbon group substituted withan alicyclic hydrocarbon group include C₁₋₆ alkyl groups substitutedwith 1 to 3 C₃₋₁₀ cycloalkyl groups such as cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl,2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl,2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl,cyclohexylpropyl, cycloheptylmethyl; C₂₋₆ alkenyl groups substitutedwith 1 to 3 C₃₋₁₀ cycloalkyl groups; C₁₋₆ alkyl groups substituted with1 to 3 C₅₋₁₀ cycloalkenyl groups; and C₂₋₆ alkenyl groups substitutedwith 1 to 3 C₅₋₁₀ cycloalkenyl groups.

As preferable examples of the aromatic heterocyclic group, mention ismade of the 5- or 6-membered aromatic monocyclic heterocyclic groupcontaining, as ring-forming atoms, besides carbon atoms, 1 to 4 atomsselected from nitrogen atom, oxygen atom and sulfur atom, such as furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; and thearomatic condensed heterocyclic group formed by condensation of (i) a 5-or 6-membered aromatic heterocyclic group containing, as ring-formingatoms, besides carbon atoms, 1 to 4 atoms selected from nitrogen atom,oxygen atom and sulfur atom with (ii) a 5- or 6-membered aromatic or anon-aromatic heterocyclic group containing, as ring-forming atoms,besides carbon atoms, 1 or 2 nitrogen atoms, benzene ring or a5-membered aromatic or a non-aromatic heterocyclic group containing, asring-forming atoms, besides carbon atoms, one sulfur atom, such asbenzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl,benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, and 1,2,4-triazolo[4,3-b]pyridazinyl.

Preferable examples of the non-aromatic heterocyclic group include a 3-to 7-membered non-aromatic heterocyclic group containing, as ringforming atoms, besides carbon atoms, 1 or 2 atoms selected from nitrogenatom, oxygen atom and sulfur atom, such as oxiranyl, azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl andpiperazinyl.

As aliphatic hydrocarbon group substituted with an aromatic heterocyclicgroup, mention is made of a C₁₋₆ aliphatic hydrocarbon group substitutedwith 1 to 3 (preferably 1 or 2) of the above-mentioned aromaticheterocyclic groups (for example, C₁₋₆ alkyl group and C₂₋₆ alkenylgroup). Preferable examples of the aliphatic hydrocarbon groupsubstituted with an aromatic heterocyclic group include C₁₋₆ alkyl groupwith 1 to 3 of, for example, furyl group, thienyl group, imidazolylgroup or pyridyl group (e.g. (2-furyl)methyl, thienylmethyl and2-(1-imidazolyl)ethyl), and C₂₋₆ alkenyl group substituted with 1 to 3of furyl group, thienyl group, imidazolyl group or pyridyl group.

As halogen atoms, mention is made of, for example, fluorine, chlorine,bromine and iodine, especially fluorine and chlorine being preferable.

As the optionally substituted amino group, mention is made of aminogroups optionally mono- or di-substituted with, for example, a C₁₋₁₀alkyl group, a C₃₋₁₀ cycloalkyl, a C₂₋₁₀ alkenyl group, a C₅₋₁₀cycloalkenyl group, a C₁₋₁₀ acyl group or a C₆₋₁₂ aromatic hydrocarbongroup (e.g. methylamino, dimethylamino, ethylamino, diethylamino,dibutylamino, diallylamino, cyclohexylamino, acetylamino,propionylamino, benzoylamino, phenylamino and N-methyl-N-phenylamino)and 4- to 6-membered cyclic amino groups (e.g. 1-azetidinyl,1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl).

The said 4- to 6-membered cyclic amino groups may optionally be furthersubstituted with (1) C₁₋₆ alkyl group, (2) C₆₋₁₄ aryl group optionallysubstituted with halogen, C₁₋₆ alkoxy group or trifluoromethyl (e.g.phenyl and naphthyl), (3) 5- or 6-membered heterocyclic groupcontaining, as ring-forming atoms, besides carbon atoms, 1 to 2 nitrogenatoms (e.g. 2-pyridyl and pyrimidinyl) or (4) 6-membered cyclic aminogroup (e.g. piperidino and 1-piperazinyl).

As the acyl group of optionally substituted acyl group, mention is madeof C₁₋₁₃ acyl groups, more specifically, besides formyl, those formed bylinkage of, for example, a C₁₋₆ alkyl group, a C₃₋₁₀ cycloalkyl group, aC₂₋₆ alkenyl group, a C₅₋₁₀ cycloalkenyl group, a C₆₋₁₂ aromatichydrocarbon group (e.g. phenyl and naphthyl) or a aromatic heterocyclicring (e.g. pyridyl) with carbonyl group, as exemplified by C₂₋₇ alkanoylgroups (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, heptanoyl and octanoyl), C₃₋₁₀cycloalkyl-carbonyl groups (e.g. cyclobutanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl and cycloheptanecarbonyl),C₃₋₇ alkenoyl groups (e.g. crotonoyl group), C₅₋₁₀ cycloalkenyl-carbonylgroups (e.g. 2-cyclohexenecarbonyl), benzoyl group and nicotinoyl group.

As substituents in the optionally substituted acyl group, mention ismade of, for example, C₁₋₃ alkyl groups, C₁₋₃ alkoxy groups, halogen(e.g. chlorine, fluorine and bromine), nitro group, hydroxyl group andamino group. The number of substituents ranges, for example, from 1 to3.

Examples of the optionally substituted hydroxyl group include hydroxylgroup, alkoxy group, cycloalkyloxy group, alkenyloxy group,cycloalkenyloxy group, aralkyloxy group, aryloxy group and acyloxygroup.

Preferable examples of the alkoxy group include C₁₋₁₀ alkoxy groups suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy,tert.-butoxy, pentyloxy, isopentyloxy, neopentyl, hexyloxy, heptyloxyand nonyloxy.

Preferable examples of the cycloalkyloxy group include C₃₋₁₀cycloalkyloxy groups such as cyclobutoxy, cyclopentyloxy andcyclohexyloxy.

Preferable examples of the alkenyloxy group include C₂₋₁₀ alkenyloxygroups such as allyloxy, crotyloxy, 2-pentenyloxy and 3-hexenyloxy.

Preferable examples of the cycloalkenyloxy group include C₅₋₁₀cycloalkenyloxy groups such as 2-cyclopentenyloxy and 2-cyclohexenyloxy.

Preferable examples of the aralkyloxy group include C₇₋₁₂ aralkyloxygroups such as C₆₋₁₄ aryl-C₁₋₆ alkoxy groups such as phenyl-C₁₋₆ alkoxygroup (e.g. benzyloxy and phenethyloxy), naphthyl-C₁₋₆ alkoxy group.

Preferable examples of the aryloxy group include a C₆₋₁₄ aryloxy groupoptionally substituted with a C₁₋₃ alkyl group, a C₁₋₃ alkoxy group,halogen, nitro group, hydroxyl group or amino group, which areexemplified, more specifically, phenoxy and 4-chlorophenoxy.

Preferable examples of the acyloxy group include C₂₋₁₅ acyloxy groupssuch as C₂₋₇ alkanoyloxy groups (e.g. acetyloxy, propionyloxy,butyryloxy and isobutyryloxy), C₆₋₁₄ aryl-carbonyloxy (e.g. benzoyloxyand naphthoyloxy).

Examples of the optionally substituted thiol group include mercaptogroup, alkylthio group, cycloalkylthio group, alkenylthio group,aralkylthio group, arylthio group, heteroarylthio group,heteroarylalkylthio group and acylthio group.

Preferable examples of the alkylthio group include C₁₋₁₀ alkylthiogroups such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, isobutylthio, sec.-butylthio, tert.-butylthio, pentylthio,isopentylthio, neopentylthio, hexylthio, heptylthio and nonylthio.

Preferable examples of the cycloalkylthio group include C₃₋₁₀cycloalkylthio groups such as cyclobutylthio, cyclopentylthio andcyclohexylthio.

Preferable examples of the alkenylthio group include C₂₋₁₀ alkenylthiogroups such as allylthio, crotylthio, 2-pentenylthio and 3-hexenylthio.

Preferable examples of the aralkylthio group include C₇₋₂₀ aralkylthiogroups such as C₆₋₁₄ arylthio groups, exemplified, more specifically, byphenyl-C₁₋₆ alkylthio (e.g. benzylthio and phenethylthio), andnaphthyl-C₁₋₆ alkylthio.

Preferable examples of the arylthio group include a C₆₋₁₄ arylthio groupoptionally substituted with a C₁₋₃ alkyl group, a C₁₋₃ alkoxy group,halogen, nitro group, hydroxyl group or amino group, such as phenylthio,naphthylthio and 4-chlorophenylthio.

As the heteroarylthio group, mention is made of, for example, themercapto group substituted with an aromatic heterocyclic group asmentioned above, especially preferable one being imidazolylthio (e.g.2-imidazolylthio) or triazoylthio (e.g. 1,2,4-triazol-5-ylthio).

As the heteroarylalkylthio group, mention is made of, for example, theabove-mentioned alkyl thio group substituted with the above-mentionedaromatic heterocyclic group. Preferable examples of the heteroarylthiogroup include pyridyl-C₁₋₆ alkylthio groups (e.g. 2-pyridylmethylthioand pyridylmethylthio).

Preferable examples of the acylthio group include C₂₋₁₅ acylthio groups,such as C₂₋₇ alkanoylthio groups (e.g. acetylthio, propionylthio,butyrylthio and isobutyrylthio), C₆₋₁₄ aryl-carbonylthio (e.g.benzoylthio and naphthoylthio).

As optionally esterified or amidated carboxyl groups, mention is made ofcarboxyl group, esterified carboxyl group and amidated carboxyl group.

Examples of the esterified carboxyl group include alkoxy carbonylgroups, aralkyloxy carbonyl groups, aryloxycarbonyl groups andheteroarylalkyloxycarbonyl groups.

Preferable examples of the alkoxycarbonyl groups include C₂₋₇alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and butoxycarbonyl.

Preferable examples of the alkoxycarbonyl group include C₈₋₂₁aralkyloxycarbonyl such as phenyl-C₂₋₇ alkoxycarbonyl (e.g.benzyloxycarbonyl) and naphthyl-C₂₋₇ alkoxycarbonyl.

Preferable examples of the aryloxycarbonyl group include, C₇₋₁₅aryloxycarbonyl groups optionally substituted with C₁₋₃ alkyl groups,C₁₋₃ alkoxy groups, halogen, nitro group, hydroxyl group or amino group,such as phenoxycarbonyl and p-tolyloxycarbonyl.

As the heteroarylalkyloxycarbonyl, mention is made of, for example, theabove-mentioned alkoxycarbonyl groups substituted with theabove-mentioned aromatic heterocyclic groups. Preferable examples of theheteroarylalkyloxycarbonyl group include pyridyl-C₂₋₇ alkoxycarbonylgroups (e.g. 2-pyridylmethoxycarbonyl and 3-pyridylmethoxycarbonyl).

As the amidated carboxyl group, mention is made of groups represented bythe formula: —CON(R¹)(R²) [wherein R¹ and R² independently stand for Hand optionally substituted hydrocarbon groups or optionally substitutedheterocyclic groups]. As the hydrocarbon group in optionally substitutedhydrocarbon groups shown by R¹ or R², mention is made of the aliphatichydrocarbon groups, alicyclic hydrocarbon groups and aromatichydrocarbon groups exemplified as substituents on the aromaticheterocyclic groups shown by R. And, as the heterocyclic group inoptionally substituted heterocyclic groups shown by R¹ or R², mention ismade of the aromatic heterocyclic groups exemplified as substituents onthe aromatic heterocyclic groups shown by R.

As substituents on the hydrocarbon groups or heterocyclic groups in R¹or R², mention is made of 1 to 3 substituents selected from halogenatoms (e.g. chlorine, fluorine, bromine and iodine), C₁₋₆ alkyl groupsand C₁₋₆ alkoxy groups.

In the general formula (I), when the aromatic heterocyclic group shownby R, the aromatic azole group shown by the cyclic group

or the substituent on ring A is an alicyclic hydrocarbon group, aromatichydrocarbon group, aliphatic hydrocarbon group substituted with aromatichydrocarbon group, aromatic heterocyclic group, non-aromaticheterocyclic group or aliphatic hydrocarbon group substituted witharomatic heterocyclic group, the said alicyclic hydrocarbon group,aromatic hydrocarbon group, the aromatic hydrocarbon group in thealiphatic hydrocarbon group substituted with an aromatic hydrocarbongroup, aromatic heterocyclic group, non-aromatic hydrocarbon group orthe aromatic heterocyclic group in the aliphatic hydrocarbon groupsubstituted with an aromatic heterocyclic group may optionally havefurther 1 to 3 (preferably 1 or 2) substituents on respectivelysubstitutable positions. Examples of such substituents includeoptionally substituted C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₂₋₆alkynyl groups, C₃₋₁₀ cycloalkyl groups, C₅₋₁₀ cycloalkenyl groups,C₆₋₁₄ aryl groups (e.g. phenyl and naphthyl), aromatic heterocyclicgroups (e.g. thienyl, furyl, pyridyl, oxazolyl, thiazolyl andtetrazolyl), non-aromatic heterocyclic groups (e.g. tetrahydrofuryl,morpholinyl, pyrrolidyl and piperazinyl), C₇₋₂₀ aralkyl groups (e.g.phenyl-C₁₋₆ alkyl groups, naphthyl-C₁₋₆ alkyl groups), amino group,N-mono(C₁₋₆)alkylamino group, N,N-di(C₁₋₆)alkylamino groups, C₂₋₇acylamino groups (e.g. C₂₋₇ alkanoylamino groups such as acetylamino andpropionylamino, and benzoylamnino group), amidino group, C₂₋₇ acylgroups (e.g. C₂₋₇ alkanoyl groups and benzoyl group), carbamoyl group,N-mono(C₁₋₆) alkylcarbamoyl groups, N,N-di(C₁₋₆)alkylcarbamoyl groups,sulfamoyl group, N-mono(C₁₋₆)alkylsulfamoyl group,N,N-di(C₁₋₆)alkylsulfamoyl group, carboxyl group, C₂₋₇ alkoxycarbonylgroups, C₈₋₂₁ aralkyloxycarbonyl groups (e.g. phenyl-C₂₋₇ alkoxycarbonyland naphthyl-C₂₋₇ alkoxycarbonyl), hydroxyl group, optionallysubstituted C₁₋₆ alkoxy groups, C₂₋₆ alkenyloxy groups, C₃₋₁₀cycloalkyloxy groups, C₅₋₁₀ cycloalkenyloxy groups, C₇₋₂₀ aralkyloxygroups (e.g. phenyl-C₁₋₆ alkoxy groups, naphthyl-C₁₋₆ alkoxy groups),C₆₋₁₄ aryloxy groups (e.g. phenoxy and naphthyloxy), mercapto, C₁₋₆alkylthio groups, C₃₋₁₀ cycloalkylthio groups, C₇₋₂₀ aralkylthio groups(e.g. phenyl-C₁₋₆ alkyl groups and naphthyl-C₁₋₆ alkylthio), C₆₋₁₄arylthio groups (e.g. phenylthio and naphthylthio), sulfo group, cyanogroup, azide group, nitro group, nitroso group, and halogen atoms (e.g.fluorine, chlorine, bromine and iodine).

As substituents in the above-mentioned optionally substituted C₁₋₆alkoxy groups and optionally substituted C₁₋₆ alkyl groups, mention ismade of, for example, 1 to 3 substituents selected from halogen atoms(e.g. fluorine, chlorine, bromine and iodine), hydroxyl group and C₁₋₆alkoxy groups.

As the substituted C₁₋₆ alkoxy groups, mention is made of, for example,trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy and1,1-difluoroethoxy.

As the substituted C₁₋₆ alkyl groups, mention is made of, for example,trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl,hydroxymethyl, methoxymethyl, 2-methoxyethyl and 2,2-dimethoxyethyl.

In the general formula (I), when the aromatic heterocyclic group shownby R, the aromatic azole group shown by the cyclic group

or the substituent on ring A is an aliphatic hydrocarbon groupsubstituted with an aliphatic hydrocarbon group or aromatic hydrocarbongroup, or an aliphatic hydrocarbon group substituted with a aromaticheterocyclic group, said aliphatic hydrocarbon group, the aliphatichydrocarbon group in the aliphatic hydrocarbon group substituted with anaromatic hydrocarbon group, or the aliphatic hydrocarbon group in thealiphatic hydrocarbon group substituted with an aromatic heterocyclicgroup may have further 1 to 3 (preferably 1 or 2) substituents atrespectively substitutable positions. Examples of these substituentsinclude non-aromatic heterocyclic groups (e.g. tetrahydrofuryl,morpholinyl, piperidyl, pyrrolidyl and piperazinyl), amino group,N-mono(C₁₋₆)alkylamino groups, N,N-di(C₁₋₆)alkylamino groups, C₂₋₇acylamino groups (e.g. C₂₋₈ alkanoylamino groups such as acetylamino andpropionylamino, and benzoylamino group), amidino group, C₂₋₇ acyl groups(e.g. C₂₋₇ alkanoyl group and benzoyl group), carbamoyl group,N-mono(C₁₋₆)alkylcarbamoyl groups, N,N-di(C₁₋₆)alkylcarbamoyl groups,sulfamoyl group, N-mono(C₁₋₆)alkylsulfamoyl groups,N,N-di(C₁₋₆)alkylsulfamoyl groups, carboxyl group, C₂₋₇ alkoxycarbonylgroups, C₈₋₂₁ aralkyloxycarbonyl groups (e.g. phenyl-C₂₋₇ alkoxycarbonylgroups and naphthyl-C₂₋₇ alkoxycarbonyl groups), hydroxyl group,optionally substituted C₁₋₆ alkoxy groups, C₂₋₆ alkenyloxy groups, C3-10cycloalkyloxy groups, C₅₋₁₀ cycloalkenyloxy groups, C₇₋₂₀ aralkyloxygroups (e.g. phenyl-C₁₋₆ alkoxy groups and naphthyl-C₁₋₆ alkoxy groups),C₆₋₁₄ aryloxy groups (e.g. phenoxy and naphthyloxy), mercapto group,C₁₋₆ alkylthio groups, C₃₋₁₀ cycloalkylthio groups, C₇₋₂₀ aralkylthiogroups (e.g. phenyl-C₁₋₆ alkyl groups, naphthyl-C₁₋₆ alkyl groups),C₆₋₁₄ arylthio groups (e.g. phenylthio and naphthylthio), sulfon group,cyano group, azide group, nitro group, nitroso group, halogen atoms(e.g. fluorine, chlorine, bromine and iodine).

As the substituents in the above-mentioned optionally substituted C₁₋₆alkoxy group, mention is made of, for example, 1 to 3 substituentsselected from halogen atoms (e.g. fluorine, chlorine, bromine andiodine), hydroxyl group, and C₁₋₆ alkoxy groups.

As the above-mentioned substituted C₁₋₆ alkoxy groups, mention is madeof, for example, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy and 1,1-difluoroethoxy.

Preferable examples of R are oxazolyl group or thiazolyl grouprespectively substituted with 1 or 2 substituents selected from (i) arylgroup optionally substituted with 1 or 2 substituents selected formhydroxyl group, alkoxy group (e.g. C₁₋₆ alkoxy group), arylalkoxy group(e.g. phenyl-C₁₋₆ alkoxy group), alkyl group (e.g. C₁₋₆ alkyl group),cyano group, halogen atom and tetrazolyl group (e.g. phenyl group andnaphthyl group), (ii) alkyl group (e.g. C₁₋₁₀ alkyl group), (iii)hydroxyalkyl group (e.g. hydroxy-C₁₋₁₀ alkyl group), (iv)alkoxycarbonylalkyl group (e.g. C₂₋₇ alkoxycarbonyl-C₁₋₁₀ alkyl group),(v) alkyl group substituted with 1 or 2 aryl groups (e.g. C₁₋₆ alkylgroup substituted with 1 or 2 phenyl groups), (vi) alkenyl groupsubstituted with 1 or 2 aryl groups (e.g. C₂₋₆ alkenyl group substitutedwith 1 or 2 phenyl group), (vii) cycloalkyl group (e.g. C₃₋₁₀ cycloalkylgroup), (viii) partially saturated naphthyl group (e.g. dihydronaphthylgroup), (ix) thienyl or furyl group optionally substituted with 1 or 2substituents selected from hydroxyl group, alkoxy group, arylalcoholgroup, alkyl group, cyano group, aryl group and halogen atom, (x)benzofuranyl group and (xi) benzothienyl, and oxazolyl group substitutedwith arylalkenyl group (e.g. phenyl-C₂₋₆ alkenyl group) and oxazolylgroup or benzoxazlolyl substituted with arylalkoxy-aryl group (e.g.phenyl-C₁₋₆ alkoxy-phenyl group) are more preferable.

Preferable examples of the cyclic group

include pyrrolyl group, imidazolyl group, pyrazolyl group, triazolylgroup, tetrazolyl group or benzimidazolyl group respectively substitutedwith 1 or 2 substituents selected from (i) alkyl group (e.g. C₁₋₁₀ alkylgroup), (ii) aryl group (e.g. phenyl group), (iii) hydroxylalkyl group(e.g. hydroxy-C₁₋₁₀ alkyl group), (iv) carboxyl group, (v)alkoxycarbonyl group (e.g. C₂₋₇ alkoxycarbonyl group) and (vi) carbamoylgroup, and imidazolyl group and triazolyl group are more preferable.

The ring A forms, depending on the kind of Y (CH or N), optionallysubstituted benzene ring or optionally substituted pyridine ring. Aspreferable examples, mention is made of optionally substituted benzenering. More preferable examples include benzene ring optionallysubstituted with 1 or 2 C₁₋₆ alkoxy groups or pyridine ring.

Preferable examples of the ring A

include

and most preferable ones are 1,3-phenylene group or 1,4-phenylene group.

X stands for oxygen atom (O), an optionally oxidized sulfur atom[S(O)_(k) (k denotes an integer of 0 to 2)], —C(═O)— or —CH(OH)—, andthe preferable examples include oxygen atom.

The symbol m denotes an integer of 0 to 10, preferable 0 to 6, morepreferably 3 to 5.

The symbol n denotes an integer of 1 to 5, preferably 1.

As salts of the compound (I) of this invention, pharmaceuticallyacceptable ones are preferable, as exemplified by salts of inorganicbases, salts of organic bases, salts with inorganic acids, salts oforganic acids, and salts of basic or acidic amino acids. Preferableexamples of salts with inorganic bases include alkali metal salts suchas sodium salt and potassium salt; alkaline earth metal salts such ascalcium salt and magnesium salt; and aluminum salt and ammonium salt.Preferable examples of salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine andN,N-dibenzylethylenediamine. Preferable examples of salts with inorganicacids include salts with hydrochloric acid, hydrobromic acid, nitricacid and phosphoric acid. Preferable examples of salts with organicacids include salts with formic acid, acetic acid, trifluoroacetic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acidand p-toluenesulfonic acid. Preferable examples of salts with basicamino acids include salts with arginine, lysine and ornithine.Preferable example of salts with acidic amino acid include salts withaspartic acid and glutamic acid. The compound (I) of this invention orsalts thereof may optionally be used as hydrates.

The compound (I) or a salt thereof of this invention [hereinaftercontaining the compound (I) or a salt thereof] can be produced by, forexample, the following methods. Additionally stating, in the followingproduction methods, not only the compounds shown by the respectiveformulae but also their salts may optionally be used. Examples of thesesalts include those set forth as the salts of the compound (I). And, ineach production method, when the product is obtained as free form, itcan be converted to the corresponding salt, and, when the product isobtained as a salt, it can be converted to the the free compound, inaccordance with conventional methods, respectively.

In the reactions described in the following, when, for example, NH₂, OHor COOH is included in the substituents, the compounds in which thesegroups are protected may optionally be employed as starting compounds,and, after completion of the reaction, the protecting group is removedto produce the object compound. As amino-protecting group, mention ismade of, for example, acyl group (e.g. C₂₋₇ alkanoyl group such asacetyl; C₂₋₇ alkoxycarbonyl such as benzyloxycarbonyl andtert.-butoxycarbonyl; phthaloyl group and hydroxyl group). Ashydroxyl-protecting group, mention is made of, for example, C₁₋₆ alkylgroups, phenyl-C₁₋₆ alkyl groups, C₂₋₇ alkanoyl groups and benzoylgroup. As carboxyl-protecting group, mention is made of, for example,C₁₋₆ alkyl group and phenyl-C₁₋₆ alkyl groups.

Incidentally stating, when the object compound contains unsaturatedbonds in the substituents, it may optionally be subjected to, forexample, conventional catalytic reduction to lead to the object compoundhaving the corresponding saturated substituents.

Method A

wherein each symbol is of the same meaning as defined above.

In this method, the compound (I) is produced by subjecting the compound(II) to condensation with the compound (III). This reaction isconducted, in accordance with a conventional method, in a solvent inertto the reaction, in the presence of an organic phosphorus compound suchas triphenylphosphine or tributylphosphine and an electrophilic agentsuch as diethyl azodicarboxylate, diisopropyl azodicarboxylate orazodicarbonyl dipiperazine. Examples of the solvent include ethers suchas diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbonssuch as chloroform and dichloromethane; aromatic hydrocarbons such asbenzene, toluene and xylene; N,N-dimethylformamide; dimethyl sulfoxide;and a mixed solvent of them. The amount of these organic phosphoruscompounds and electrophilic agents to be employed ranges, preferablyfrom 1 to 5 molar equivalents relative to the compound (II). The amountof the compound (III) to be employed ranges, preferably from 1 to 10molar equivalents relative to the compound (II). This reaction isconducted usually at temperatures ranging from −50 to 150° C.,preferably from about −1 to 100° C. over a period ranging from 0.5 to 20hours. The compound (I) thus obtained can be isolated and purified by aknown isolating and purifying means such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phasic transfer and chromatography.

Method B

wherein W stands for a leaving group, and other symbols are of the samemeaning as defined above.

Examples of the leaving group shown by W include halogen atoms and agroup shown by the formula: —OSO₂R³, R³ stands for an aryl groupoptionally substituted with a C₁₋₆ alkyl group such as methyl and ethylor p-tolyl (e.g. phenyl group optionally substituted with a C₁₋₆ alkylgroup).

In this method, the compound (I) is produced by subjecting the compound(IV) to condensation with the compound (III). This reaction is conductedin accordance with a conventional method, in a solvent inert to thereaction in the presence of a base. Examples of the solvent includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone;halogenated hydrocarbons such as chloroform and dichloromethane;N,N-dimethylformamide; dimethyl sulfoxide; and a mixed solvent of them.Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate and potassiumcarbonate; amines such as pyridine, triethylamine and N,N-dimethylaniline; metal hydrides such as potassium hydride and sodium hydride;and sodium methoxide, sodium ethoxide and tert.-butoxide. The amount ofthese bases to be employed ranges, preferably, from 1 to 5 molarequivalents relative to the compound (IV). The amount of the compound(III) to be employed ranges, preferably, from about 1 to 10 molarequivalents relative to the compound (IV). This reaction is conducted attemperatures usually ranging from −50 to 150° C., preferably from about−10 to 100° C., over a period ranging from 0.5 to 20 hours. The compound(I) thus obtained can be isolated and purified by a known isolating andpurifying means such as concentration, concentration under reducedpressure, solvent extraction, crystallization, recrystallization, phasictransfer and chromatography.

Method C

wherein X¹ stands for oxygen atom or sulfur atom, W¹ stands for aleaving group, and other symbols are of the same meaning as definedabove.

Examples of the leaving group shown by W¹ include halogen atoms and agroup shown by the formula: —OSO₂R⁴, R⁴ stands for an aryl groupoptionally substituted with a C₁₋₆ alkyl group such as methyl and ethylor p-tolyl (e.g. phenyl group optionally substituted with a C₁₋₆ alkylgroup).

In this method, the compound (V) is allowed to react with the compound(VI) to produce the compound (Ia). This reaction is conducted in asolvent inert to the reaction, in the presence of a base. Examples ofthe solvent include ethers such as tetrahydrofuran and dioxane; aromatichydrocarbons such as toluene and xylene; N,N-dimethylformamide, dimethylsulfoxide, acetone or water; and a mixed solvent of them. Examples ofthe base include potassium carbonate, sodium hydrogencarbonate, sodiummethoxide, sodium ethoxide, sodium hydride, potassium hydroxide, sodiumhydroxide and lithium hydroxide. The amount of the compound (VI) to beemployed ranges from about 1 to 10 molar equivalents relative to thecompound (V). This reaction is conducted at temperatures ranging usuallyfrom −20 to 15° C., preferably from about 0 to 100° C. over a periodranging from 1 to 20 hours. The compound (Ia) thus obtained can beisolated and purified by a known isolating and purifying means such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer and chromatography.

Method D

It is also possible that the compound (Ic), which is a compound (I)wherein R and/or

is a group having an optionally esterified carboxyl group, is subjectedto reduction to give the compound (Id), which is a compound (I) whereinR and/or

is a group having hydroxymethyl group. This reduction can be conductedby a per se known means, for example, reduction using a metal hydride, ametal hydride complex compound, diborane or a substituted borane. Morespecifically, this reaction is conducted by processing the compound (Ic)with a reducing agent. Examples of the reducing agent include alkalimetal borohydrides (e.g. sodium borohydride and lithium borohydride),metal hydride complex compounds such as lithium aluminum hydride,organotin compounds such as triphenyltin hydride, and diborane. Thisreaction is conducted in an organic solvent inert to the reaction. Asthe solvent, use is made of, for example, aromatic hydrocarbons such asbenzene, toluene and xylene, halogenated hydrocarbons such aschloroform, dichloromethane and carbon tetrachloride, ethers such astetrahydrofuran and dioxane, alcohol such as methanol and ethanol,N,N-dimethylformamide or a mixed solvent of them, suitably depending onkinds of the reducing agent then employed. This reaction is conducted attemperatures ranging usually from −20 to 150° C., preferably from about0 to 100° C. over a period ranging from 0.1 to 10 hours. The compound(Id) thus obtained can be isolated and purified by a known isolating andpurifying means such as concentration, concentration under reducedpressure, solvent extraction, crystallization, recrystallization, phasictransfer and chromatography.

Method E

It is also possible that the compound (Ie), which is a compound (I)wherein R and/or

is a group having cyano group is allowed to react with an azide compoundto give the compound (If), which is a compound (I) wherein R and/or

is a group having 1H-tetrazol-5-yl group. This reaction can be conductedby a per se known method. For example, the reaction is conducted, inaccordance with the method described in Journal of American ChemicalSociety Vol.80 p.3908 (1957), by the reaction with sodium azide andammonium chloride in N,N-dimethylformamide. The amounts of sodium azideand ammonium chloride are respectively 1 to 7 molar equivalents,preferably 1 to 5 molar equivalents, relative to the compound (Ie). Thisreaction is conducted at temperatures ranging usually from 0 to 180° C.,preferably from 50 to 150° C. over a period ranging from 1 to 48 hours.And, this reaction can be conducted also, in accordance with the methoddescribed in Journal of organic Chemistry Vol.56 p.2395 (1991), by thereaction with trimethyltin azide or tributyltin azide, followed bytreating with an acid. The compound (If) thus obtained can be isolatedand purified by a known separating and purifying means such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer and chromatography.

Method F

It is also possible that the compound (Ih), which is the compound (I)wherein X is oxidized sulfur atom [S(O)_(k) (wherein k denotes 1 or 2)],by subjecting the compound (Ig), which is the compound (I) wherein X isoxidized sulfur atom [S(O)_(k) (wherein k denotes 0)], to oxidation.This reaction is conducted by oxidizing the compound (Ig) with anoxidizing agent. As the oxidizing agent, use is made of, for example,m-chloroperbenzoic acid, hydrogen peroxide, peresters and sodiummetaperiodate. This reaction is conducted in an organic solvent inert tothe reaction. As the solvent, use is suitably made of, depending on thekinds of the oxidizing agent then employed, aromatic hydrocarbons suchas benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride; alcohols such asmethanol and ethanol; or a mixed solvent of them. When the oxidizingagent is used in the equimolar or less amount relative to the compound(Ig), the compound (Ih) wherein k=1 is produced preferentially. When theoxidizing agent is used in an excess equimolar amount relative to thecompound (Ig), the compound (Ih) wherein k=2 is produced preferentially.This reaction is conducted usually at temperatures ranging from 50 to+100° C., preferably from −20 to +50° C. over a period of 0.5 to 10hours. The compound (Ih) thus obtained can be isolated and purified by aknown separating and purifying means such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer and chromatography.

Method G

It is also possible that the compound (Ij), which is the compound (I)wherein X is —CH(OH)—, can be produced by subjecting the compound (Ii),which is the compound (I) wherein X is —C(═O)—, to reduction. Thisreaction is conducted by processing the compound (Ii) with a reducingagent. As the reducing agent, use is made of, for example, alkali metalborohydrides such as sodium borohydride and lithium borohydride; metalhydride complex compounds such as lithium aluminum hydride; anddiborane. This reaction is conducted in an organic solvent inert to thereaction. As the solvent, use is suitably made of, depending on thekinds of the reducing agent then employed, aromatic hydrocarbons such asbenzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride; ethers such astetrahydrofuran and dioxane; alcohols such as methanol and ethanol;N,N-dimethylformamide or a mixed solvent of them. This reaction isconducted at temperatures usually ranging from −20 to +150° C.,preferably from 0 to +100° C., over a period of 0.5 to 10 hours. Thecompound (Ij) thus obtained can be isolated and purified by a knownseparating and purifying means such as concentration, concentrationunder reducing pressure, solvent extraction, crystallization,recrystallization, phasic transfer and chromatography.

Method H

It is also possible that the compound (Im), which is the compound (I)wherein R is alkoxy group, can be produced by subjecting the compound(Ik), which is the compound (I) wherein R is hydroxyl group. Thisreaction is conducted in substantially the same manner as in Method A orC. The compound (Im) thus obtained can be isolated and purified by aknown separating and purifying means such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phasic transfer and chromatography.

Method I

It is also possible that the compound (Io), which is the compound (I)wherein R is alkoxy, can be produced by allowing the compound (In),which is the compound (I) wherein R is halogen or a group havingsulfonyloxy group, to react with aryl boric acid. This reaction isconducted by a known method per se, for example, in the presence of ametal catalyst such as zero-valent palladium or zero-valent nickel and abase in accordance with a method described in Journal of OrganicChemistry Vol. 58, 2201 (1993) or Journal of Organic Chemistry Vol. 60,1060 (1955). As the palladium catalyst, use is made of, for example,tris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium; as the nickel catalyst, used ismade of, for example, 1,1′-bis(diphenylphosphino) ferrocen nickel, etc.As the base, use is made of, for example, sodium hydrogen carbonate,sodium carbonate, potassium carbonate, tripotassium phosphate. Thisreaction is conducted in an organic solvent inert to the reaction. Asthe solvent, use is made of, for example, benzene, toluene, methanol,ethanol, tetrahydrofuran, dioxan and water, or a mixed solvent of them,suitably depending on kinds of the metal catalyst then employed. Theamount of aryl boric acid to be employed is 1-7 molar equivalents,preferably 1-5 molar equivalents relative to the compound (In). Theamount of the metal catalyst to be employed is 0.01-1 molar equivalent,preferably 0.05-0.5 molar equivalents. This reaction is usuallyconducted at −20-+150° C., preferably 0-100° C. for 0.1-24 hours. Thecompound (Io) thus obtained can be isolated and purified by a knownisolation and purification mean such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phasic transfer and chromatography.

The compound (II) to be employed in Method A can be synthesized by, forexample, the method as shown below.

(1) When X is oxygen atom or sulfur atom:

wherein each symbol is of the same meaning as defined above.

This reaction is to synthesize the compound (IIa) by subjecting thecompound (VII) and the compound (VI) to condensation. This reaction isconducted in substantially the same manner as in Method C.

Incidentally, it is preferable that the hydroxyl group of —(CH₂)_(m)—OHin the compound (VII) is protected, then the compound (VII) is subjectedto condensation with the compound (VI), and the protective group isremoved after completing the reaction.

(2) When X is oxidated sulfur atom [S(O)_(k) (wherein k denotes 1 or2)]:

wherein each symbol is of the same meaning as defined above.

This reaction is a method of synthesizing the compound (IIc) bysubjecting the compound (IIb) to oxidation. This reaction is conductedin substantially the same manner as in Method F.

The compound (IIb) employed herein can be obtained by allowing theafore-mentioned compound (VII) to react with the compound (VI).

(3) When X is —C(═O)—:

wherein R⁵ stands for a C₁₋₆ alkyl group or a phenyl-C₁₋₆ alkyl group,W² stands for a halogen atom and other symbols are of the same meaningas defined above.

This reaction is a method to synthesize the compound (IId) by condensingthe compound (VIII) with the compound (IX), followed by decarboxylation.In this reaction, at first, the compound (VIII) is condensed with thecompound (IX) in a solvent in the presence of a base. Examples of thesolvent include aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as tetrahydrofuran and dioxane; alcohols such asmethanol and ethanol; N,N-dimethylformamide, dimethylsulfoxide; or amixed solvent of them. As the base, mention is made of, for example,sodium hydroxide, potassium hydroxide, sodium methoxide, sodiumethoxide, potassium t-butoxide, sodium hydride and potassium hydride.The amount of the base to be employed ranges from about 1 to 5 molarequivalents relative to the compound (VIII). This reaction is conductedat temperatures ranging usually from −20 to +150° C., preferably from 0to +100° C. over a period of 0.5 to 10 hours.

Then, the condensed product obtained thus above was subjected tohydrolysis, which was then subjected to decarboxylation to synthesizethe compound (IId). The hydrolysis is conducted, in accordance with aper se known method, in a hydrous solvent in the presence of an acid ora base. The carboxylic acid compound thus obtained is subjected todecarboxylation after isolation or without isolation to produce thecompound (IId). This decarboxylation reaction is conducted in a solventunder heating. Examples of the solvent include aromatic hydrocarbonssuch as benzene, toluene and xylene; halogenated hydrocarbons such asdichloromethane, chloroform and carbon tetrachloride; ethers such astetrahydrofuran and dioxane; alcohols such as methanol and ethanol;N,N-dimethylformamide, dimethylsulfoxide, pyridine, water; or a mixedsolvent of them. This reaction is conducted at temperatures rangingusually form +50 to +250° C., preferably from +70 to +150° C. over aperiod of 5 to 24 hours.

The compound (VIII) employed herein can be synthesized by, for example,the method as shown below.

wherein W³ stands for a halogen atom; R⁶ stands for a C₁₋₆ alkyl groupor phenyl-C₁₋₆ alkyl group; and other symbols are of the same meaning asdefined above.

This reaction is a method to synthesize the compound (VIII) bycondensing the compound (X) with the compound (XI), followed bydecarboxylation. In this reaction, at first, the compound (X) iscondensed with the compound (XI) in a solvent in the presence of a base.Examples of the solvent include aromatic hydrocarbons such as benzene,toluene and xylene; ethers such as tetrahydrofuran and dioxane; alcoholssuch as methanol and ethanol; N,N-dimethylformamide, dimethylsulfoxide;or a mixed solvent of them. As the base, mention is made of, forexample, magnesium ethoxide. The amount of the base to be employedranges from about 1 to 5 molar equivalents relative to the compound(XI). This reaction is conducted at temperatures ranging usually from−20 to +150° C., preferably from 0 to +100° C. over a period of 0.5 to10 hours.

Subsequently, the condensed product thus obtained is subjected tohydrolysis, followed by decarboxylation to synthesize the compound(VIII). This hydrolysis and decarboxylation are conducted insubstantially the same manner as in the hydrolysis and decarboxylationafter the condensation of the compound (VIII) with the compound (IX).

Incidentally, it is also possible that the compound (VIII) is obtainedby subjecting the compound (XI) to condensation after protecting thehydroxyl group of —(CH₂)_(m)—OH in the compound (X) and by subjectingthe condensate to decarboxylation, followed by removing the protectivegroup; or, without subjecting the compound (VIII), in which the hydroxylgroup is protected, to deprotecting reaction, by subjecting the compound(VIII) to condensation with the compound (IX) and decarboxylation,followed by removing the protective group.

wherein each symbol is of the same meaning as defined above.

This reaction is a method of synthesizing the compound (IIe) bysubjecting the compound (IId) to reduction. This reaction is conductedin substantially the same manner as in Method G.

The compound (IV) to be employed in Method B can be synthesized by, forexample, the method as shown below.

(II)-→(IV)

This reaction is a method of synthesizing the compound (IV) by allowinga halogenizing agent of sulfonylating agent to react with the compound(II). As the halogenating agent, use is made of, for example,hydrochloric acid, thionyl chloride or phosphorus tribromide, and, inthis case, the compound (IV), in which W is halogen (e.g. chlorine orbromine), is produced. This reaction is conducted in a solvent such asbenzene, toluene, xylene, dichloromethane or chloroform, or using anexcess amount of a halogenating agent as the solvent, at temperaturesranging from −20 to +100° C. over a period of 5 to 24 hours. The amountof the halogenating agent to be employed ranges from 1 to 10 molarequivalents relative to the compound (II). As the sulfonylating agent,use is made of, for example, methanesulfonyl chloride, benzene sulfonylchloride and p-toluenesulfonyl chloride. The compound (IV), in which Wis a group represented by the formula: —OSO₂R³ (wherein R³ is of thesame meaning as defined above), for example, methanesulfonyloxy,benzenesulfonyloxy or p-toluenesulfonyloxy, is produced. This reactionis conducted in a solvent such as benzene, toluene, xylene,dichloromethane, chloroform and ethyl acetate in the presence of a baseat temperatures ranging from −20 to +100° C. over a period of 5 to 24hours. Examples of the base include triethylamine, N-methyl morpholine,sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonateand potassium carbonate. The amount of the base to be used ranges from 1to 10 molar equivalents relative to the compound (II).

The compound (V) to be employed in Method C can be synthesized by, forexample, a method as shown below.

wherein W⁴ stands for a leaving group, and other symbols are of the samemeaning as defined above.

As the leaving group shown by W⁴, mention is made of, for example,halogen atoms and groups represented by the formula: —OSO₂R⁷ wherein R⁷stands for a C₁₋₆ alkyl group such as methyl and ethyl, or an optionallysubstituted aryl group such as p-tolyl (e.g. phenyl group optionallysubstituted with a C₁₋₆ alkyl group).

This reaction is a method of synthesizing the compound (V) by subjectingthe compound (XII) to condensation with the compound (III). Thisreaction is conducted in substantially the same manner as in Method B.

The compound (I) of this invention or salts thereof are relatively lowin toxicity and can be used as such or as a medicinal composition, formammals including man (e.g. horse, cow, dog, cat, rat and mouse, rabbit,pig and monkey), prepared by mixing with a per se known pharmaceuticallyacceptable carrier or the like. And, in the medicinal composition,besides the compound (I) of this invention or a salt thereof, any otheractive component such as the following hormone therapeutic agents,chemotherapeutic agents and immunotherapeutic agents may optionally beallowed to be present.

The administration of the compound (I) or a salt thereof as a medicineto mammals including man is usually performed orally in the form of, forexample, tablets, capsules (including soft capsules and microcapsules),powdery preparations and granular preparations, and, depending on cases,non-orally in the form of, for example, injections, suppositories andpellets. The dosage of the compound (I) or a salt thereof for a patient(40 to 80 kg body weight) having breast cancer or prostatic cancerranges, while varying with the administration routes, symptoms or thelike, in the case of oral administration, preferably from 1.0 to 100mg/kg, more preferably from 5 to 50 mg/kg per day. This amount can beadministered once daily or dividing into two to three times a day.

The compounds (I) and (II) or their salts of this invention, mixed withpharmaceutically acceptable carriers, can be administered orally ornon-orally in the form of solid preparations such as tablets, capsules,granules and powdery preparations; or in the form of liquid preparationssuch as syrups and injections.

As pharmaceutically acceptable carriers, use is made of conventionalorganic or inorganic carriers for pharmaceutical preparations, morespecifically, for example, excipients, lubricants, binders anddisintegrators for solid preparations; and solvents, solubilizers,suspending agents, isotonizers, buffering agents and local anestheticagents for liquid preparations. And, upon necessity, such additives asantiseptics, antioxidants, colorants and sweetners are further used.

Preferable examples of excipients include lactose, sucrose, D-mannitol,starch, crystalline cellulose and light silicon dioxide.

Preferable examples of lubricants include magnesium stearate, calciumstearate, talc and colloid silica.

Preferable examples of binders include crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidine.

Preferable examples of disintegrators include starch, carboxymethylcellulose, carboxymethyl cellulose calcium, croscarmellose sodium andcarboxymethyl starch sodium.

Preferable examples of solvents include distilled water for injection,alcohol, propylene glycol, macrogol, sesame oil and corn oil.

Preferable examples of solubilizers include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodiumcitrate.

Preferable examples of suspending agents include surfactants such asstearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride and glycerinmonostearate; and hydrophilic polymers such as polyvinyl alcohol,polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcellulose.

Preferable examples of isotonizers include sodium chloride, glycerin andD-mannitol.

Preferable examples of buffering agents include buffer solutions ofphosphates, acetates, carbonates and citrates.

Preferable examples of local anesthetic agents include benzyl alcohol.

Preferable examples of antiseptics include para-hydroxybenzoic acidesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid and sorbic acid.

Preferable examples of antioxidants include sulfites and ascorbic acid.

The pharmaceutical preparation of this invention can be formulated,while varying with for example forms, administration routes andcarriers, in accordance with a conventional method, by allowing thecompound (I) of this invention or a salt thereof to be contained in anamount of 0.1 to 90% (w/w) relative to the total weight of thepreparation.

And, the compound (I) of this invention can be administered to the samesubject simultaneously with any other agents of hormone therapy,chemotherapy or immunotherapy, or it can be administered to the samesubject with a time lag.

Examples of the hormone therapeutic agents include estrogen preparationsor estrogen antagonistic preparations (e.g. tamoxifen), androgenpreparations or androgen antagonistic preparations (e.g. flutamide), orLH-RH analog (e.g. leuprorelin, goserelin) or LH-RH antagonist.

Examples of the chemotherapeutic agents include alkylating agent (e.g.cyclophosphamide, iphosphamide), matabolic antagonists (e.g.methotrexate, 5-fluorouracil), antitumor antibiotics (e.g. mitomycin,adriamycin), and antineoplastic agents derived from plants (e.g.vincristine, vindesine, taxol), cisplatin, carboplatin and etoposide.

Examples of immunotherapeutic agents include microorganisms or cellcomponents (e.g. muramyl dipeptide derivatives, pycivanyl),polysaccharides having immunostimulant activity (e.g. lentinan,sizofiran, krestin), cytokines obtained by means of genetic engineering(e.g. interferon, interleukin).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be illustrated in further detail in thefollowing Test Examples, Formulation Examples, Reference Examples andWorking Examples, which are not intended to limit this invention withinthe scope of these Examples.

Elution in the column chromatography conducted in Reference Examples andWorking Examples was carried out while monitoring with TLC (Thin LayerChromatography). In the TLC monitoring, as the TLC plate, use was madeof 60F₂₅₄ (70 to 230 mesh) plates manufactured by Merck & Co., Inc., asthe developing solvent, use was made of the same solvent as employed foreluting in the column chromatography, and the detection was conductedwith a UV detector. The silica gel for the column was Kieselguhr 60F₂₅₄(70 to 230 mesh) manufactured by Merck & Co. Inc. NMR spectra showproton NMR and were measured using tetramethylsilane as the internalstandard with VARIAN Gemini-200 (270 MHZ type spectrometer). All δvalues were expressed in ppm. And, the abbreviations used in WorkingExamples have the following meanings.

s:singlet, br:broad, d:doublet, t:triplet, q:quartet, dd:double doublet,dt:double triplet, ddd:doublet doublet doublet, m:multiplet, J:couplingconstant, Hz:Hertz.

In the Test Examples, compound number means Working Example number (forexample, the compound of Working Example 2 is expressed as Compound 2)

[WORKING EXAMPLES] Test Example 1 Inhibition of the Activity of HumanGrowth Factor Receptor Tyrosine Kinases

As enzyme standard, the tyrosine kinase domain of the human HER2 genewas cloned to prepare the recombinant gene of insect virus vector, withwhich the insect cell line SF-21 was infected to produce an enzymeprotein (Guy P. M. et al., Journal of Biological Chemistry Vol. 267,pp.13851-13856, 1992). As substrate, the phosphorylated tyrosine domainof the HER3 protein was cloned to prepare the recombinant gene ofplasmid vector with which Escherichia Coli strain JM109 was infected togive an enzyme protein (Sierke S. L. et al., Biochemistry Vol. 32,pp.10102-10108, 1993). The enzymatic reaction was performed by theenzyme-linked immunological method which consisted of fixing thesubstrate protein in wells of a 96-well microtiter plate, adding theenzyme into the wells and quantitating phosphorylated tyrosine, whichwas the reaction product, by use of the anti-phosphorylated tyrosineantibody (Cleaveland J. S. et al., Analytical Biochemistry Vol. 190,pp249-253, 1990). The results were expressed in terms of IC₅₀, theconcentration of the compound which inhibited the phosphorylation oftyrosine by 50%, designating the phosphorylation of tyrosine in thecontrol which did not contain the compound solution as 100%.

The results are shown in [Table 1].

TABLE 1 Inhibition of the HER2 receptor type tyrosine kinase activityConcentration of inhibiting Compound HER2 (IC₅₀ ^(, μM)) 2 67 8 20

Test Example 2 Inhibition of Phosphorylation of Receptor Tyrosine inHuman Breast Cancer Cells (1)

Human breast cancer cell line T-47D was cultured for 7 days in themedium containing 0.1% bovine fetus albumin instead of serum to deprivethe medium of estrogen. On the 7th day, 1,000 μl of the cell suspension(250,000 cells) was seeded in each well of the 24-well plates. Theculture were incubated at 37° C. in a 5% carbon dioxide gas incubator.On the next day, 100 μl of the 10-fold serial dilution of each compoundsolution was added to each well and, 2 hours later, 0.5 μg/ml ofheregulin was added to it. After 5 minutes the extract solution wasadded to it to terminate the reaction, and the protein fraction wasextracted. To the extract was added an antibody against the humanreceptor type oncogene HER2 to precipitate the human receptor typeoncogene HER2 protein by the reaction of immunoprecipitation. Theprecipitate was fractionated by the protein electrophoresis. The proteinin the electrophoretic gel was transferred to a nylon filter. The filterwas allowed to react with the phosphorylated tyrosine-specific antibody.The reaction product was fluorescence-labeled to expose a photofilm. Theintensity of the exposure on the photofilm was quantitated by animage-analyzing apparatus. The proportion of the phosphorylation of HER2tyrosine in the cells added with a compound solution of eachconcentration was calculated designating the phosphorylation of HER2tyrosine in the heregulin-added cells as 100%.

The results are shown in [Table 2]. Compound 8 of the present inventionhas been shown to inhibit dose-dependently the phosphorylation reactionof the tyrosine residue in the receptor protein which was induced byactivation of the receptor tyrosine kinase accompanied with thestimulation of the growth factors when human mammary cancer cells werestimulated by a growth factor heregulin.

TABLE 2 Inhibition of phosphorylation of receptor tyrosine residueConcentration of Compound 8 (μM) 0 0.4 1.6 6.3 25 Phosphorylation of the100 62 52 33 20 tyrosine residue (%)

Test Example 3 Inhibition of Phosphorylation of Receptor Tyrosine inHuman Breast Cancer Cells (2)

Human breast cancer cell line MCF-7 was used. 1,000 μl of the cellsuspension (250,000 cells) was seeded in each well of the 24-wellplates. The culture were incubated at 37° C. in a 5% carbon dioxide gasincubator. On the next day, 100 μl of the 10-fold serial dilution ofeach compound solution was added to each well and, 2 hours later, 0.5μg/ml of heregulin was added to it. After 5 minutes the extract solutionwas added to it to terminate the reaction, and the protein fraction wasextracted. The protein was fractionated by the protein electrophoresis.The protein in the electrophoretic gel was transferred to a nylonfilter. The filter was allowed to react with the phosphorylatedtyrosine-specific antibody. The reaction product wasfluorescence-labeled to expose a photofilm. The intensity of theexposure on the photofilm was quantitated by an image-analyzingapparatus. The proportion of the phosphorylation of HER2 tyrosine in thecells added with a compound solution of each concentration wascalculated designating the phosphorylation of HER2 tyrosine in theheregulin-added cells as 100%.

The results are shown in [Table 3]. Compound (I) of the presentinvention has been shown to inhibit dose-dependently the phosphorylationreaction of the tyrosine residue in the receptor protein which wasinduced by activation of the receptor tyrosine kinase accompanied withthe stimulation of the growth factors when human mammary cancer cellswere stimulated by a growth factor heregulin.

TABLE 3 Phosphorylation of receptor tyrosine residue (%) Concentrationof Compounds (μM) 0 0.4 1.6 6.3 25 Compound 8 100 67 41 32 30 Compound72 100 96 48 19  7 Compound 80 100 46 40 34 Compound 94 100 93 86 45 25Compound 109 100 92 89 43 31

Test Example 4 In vitro Inhibition of Cell Proliferation (1)

100 μl (containing 2,000 cells) of a cell suspension of human breastcancer cell line MDA-MB-453 was seeded in each well of the 96-wellmicrotiter plates. The cultures were incubated at 37° C. in a 5% carbondioxide gas incubator. On the next day, 100 μl of the 2-fold serialdilution of each compound solution was added to each well and themixtures were cultured for 3 days. The solution containing the compoundwas removed and the cells were washed with water. To the cells was addeda 0.4% (W/V) dye SRB (dissolved in 1% acetic acid) solution to fix andstain the cell protein (Skehan P. et al., Journal of the National CancerInstitute Vol.82, pp.1107-1112, 1990). The dye solution was removed andthe fixed and stained cell protein was washed. The protein-bound dye wasextracted with 200 μl of 10 mM Tris buffer. The optical density of theextracted dye was determined at the wavelength of 540 nm to estimate thequantity of the cells in terms of the protein quantity. Designating theprotein quantity in the control to which no compound solution was addedas 100%, the proportion of the residual protein quantity in each treatedgroup was calculated, and IC₅₀, which was concentration of the compoundrequired to inhibit the residual protein quantity to 50% the quantity ofthe control, was calculated.

The results are shown in [Table 4].

TABLE 4 Inhibition of cell proliferation IC₅₀ (μM) Compound Breastcancer MDA-MB-453 2 0.66 8 0.25

Test Example 5 In vitro Inhibition of Cell Proliferation (2)

100 μl (containing 2,000 cells) of a cell suspension of human breastcancer cell line MDA-MB-453 was seeded in each well of the 96-wellmicrotiter plates. The cultures were incubated at 37° C. in a 5% carbondioxide gas incubator. On the next day, 100 μl of the 2-fold serialdilution of each compound solution was added to each well and themixtures were cultured for 3 days. The solution containing the compoundwas removed and the cells were washed with water. To the cells was addeda 0.4% (W/V) dye SRB (dissolved in 1% acetic acid) solution to fix andstain the cell protein (Skehan P. et al., Journal of the National CancerInstitute Vol.82, pp.1107-1112, 1990). The dye solution was removed andthe fixed and stained cell protein was washed. The protein-bound dye wasextracted with 200 μl of 10 mM Tris buffer. The optical density of theextracted dye was determined at the wavelength of 540 nm to estimate thequantity of the cells in terms of the protein quantity. Designating theprotein quantity in the control to which no compound solution was addedas 100%, the proportion of the residual protein quantity in each treatedgroup was calculated, and IC₅₀, which was concentration of the compoundrequired to inhibit the residual protein quantity to 50% the quantity ofthe control, was calculated.

The results are shown in [Table 5].

TABLE 5 Inhibition of cell proliferation IC₅₀ (μM) Compound Breastcancer MDA-MB-453 72 1.7 80 0.09 94 4.8 109  2.5

Test Example 6 Selective in vitro Inhibition of Breast Cancer CellGrowth

100 μl (containing 2,000 cells) of a cell suspension of various humanbreast cancer cell lines shown in [Table 6] was seeded in each well ofthe 96-well microtiter plates. The cells were incubated at 37° C. in a5% carbon dioxide gas incubator. Next day, 100 μl of a 2 fold serialdilution of a compound solution was added to each well. The cultureswere incubated for 3 days. The solution containing the compound wasremoved and the cells were washed with water. To the cells was added a0.4% (V/W) dye SRB (dissolved in 1% acetic acid) solution to fix andstain the cell protein. The dye solution was removed and the fixed andstained cell protein was washed. The protein-bound dye was extractedwith 200 μl of 10 mM Tris buffer. The optical density of the extracteddye was determined at the wavelength of 540 nm to estimate the quantityof the cells in terms of the protein quantity. Designating the proteinquantity in the control to which no compound solution was added as 100%,the proportion of the residual protein quantity in each treated groupwas calculated, and IC₅₀, which was the concentration of the compoundrequired to inhibit the residual protein quantity to 50% the quantity ofthe control, was calculated.

The results are shown in [Table 6]. Compound 8 of the present inventionhas been shown to inhibit specifically the cell growth of human mammarycancer cell line.

TABLE 6 Inhibition of cell proliferation of various cell lines IC₅₀ forCell Compound 8 Cancer lines (μM) Mammary cancer MDA-MB-453 0.25MDA-MB-468 0.52 BT-20 0.52 BT-474 0.29 SKBR3 1.0 T-47D 0.57 Pancreaticcancer ASPC-1 2.5 Epidermal cancer HSC-1 2.1 Large intestinal WiDr 2.1cancer Normal MRC5 15

Test Example 7 Selective in vitro Inhibition of Breast Cancer andProstate Cancer Cell Growth

100 μl (containing 2,000 cells) of a cell suspension of various humancancer cell lines shown in [Table 7] was seeded in each well of the96-well microtiter plates. The cells were incubated at 37° C. in a 5%carbon dioxide gas incubator. Next day, 100 μl of a 2 fold serialdilution of a compound solution was added to each well. The cultureswere incubated for 3 days. The solution containing the compound wasremoved and the cells were washed with water. To the cells was added a0.4% (V/W) dye SRB (dissolved in 1% acetic acid) solution to fix andstain the cell protein. The dye solution was removed and the fixed andstained cell protein was washed. The protein-bound dye was extractedwith 200 μl of 10 mM Tris buffer. The optical density of the extracteddye was determined at the wavelength of 540 nm to estimate the quantityof the cells in terms of the protein quantity. Designating the proteinquantity in the control to which no compound solution was added as 100%,the proportion of the residual protein quantity in each treated groupwas calculated, and IC₅₀, which was the concentration of the compoundrequired to inhibit the residual protein quantity to 50% the quantity ofthe control, was calculated.

The results are shown in [Table 7]. Compound (I) of the presentinvention has been shown to inhibit specifically the cell growth ofhuman mammary cancer cell line.

TABLE 7 Inhibition of cell proliferation of various cell lines IC₅₀ forCompounds (μM) Cancer Cell lines 72 80 94 109 Breast cancer MDA-MB-4531.7 0.09 4.8 2.5 T-47D 3.5 MCF-7 0.62 0.01 1.1 0.19 Prostate cancerLNCaP 7.9 1.6 5.6 11 PC3 9.5 6.5 15 16 Normal MRC5 >25 >25 >25 >25

As seen in Tables 1, 2, 3, 4, 5, 6 and 7, the compounds of the presentinvention have been shown to inhibit growth factor stimulated activationof tyrosine kinases in the receptor. They have no adverse effects on theproliferation of normal cells and inhibit the proliferation of tumorcells, especially of mammary and prostate cancer cells.

Test Example 8 In vivo Mammary Cancer Inhibiting Effect (1)

5,000,000 cells of human breast cancer cell line, MDA-MB-453, weresuspended in a gelmatrix solution. The suspension was subcutaneouslyimplanted at the breast in 7-week-old female Balb/C strain athymic nudemice (Friedman R. et al., Proceedings of the National Academy ofSciences of the U.S.A. Vol. 87, pp.6698-6702, 1990). Twelve days afterthe implantation, the diameters of tumors were determined. For theexperiment were used 5 mice per group with similar tumor size. Compound8 of the present invention was suspended in a 5% gum arabic solution(physiological saline) and administered orally twice daily in dose of 30mg/kg body weight for 10 days, or 2 cycle oral administrationsconsisting of 45 mg/kg body weight twice daily for 3 days and notreatment for 3 days were performed. On the day when the dosing wasended, the diameters of tumors were measured. Tumor volume wascalculated by the following formula: volume of tumor=longestdiameter×shortest diameter×shortest diameter×½. The growth rate oftumors was obtained as the proportion to the volume of tumor in thecontrol animals in which only the gum arabic solution was administered.The body weights of mice administered with Compound 8 of the presentinvention were measured during the experiment to observe no decrease.

The results are shown in [Table 8].

TABLE 8 Inhibition of athymic nude mice implanted cancer growth Dose ofcompound Tumor growth (mg/kg/day) rate (%)  0 100  60 71 90 46

Compound 8 of the present invention inhibited dose-dependently thegrowth of human breast cancer implanted to athymic nude mice.

Test Example 9 In vivo Mammary Cancer Inhibiting Effect (2)

5,000,000 cells of human breast cancer cell line, MDA-MB-453, weresuspended in a gelmatrix solution. The suspension was subcutaneouslyimplanted at the breast in 7-week-old female Balb/C strain athymic nudemice (Friedman R. et al., Proceedings of the National Academy ofSciences of the U.S.A. Vol. 87, pp.6698-6702, 1990). Twelve days afterthe implantation, the diameters of tumors were determined. For theexperiment were used 5 mice per group with similar tumor size. Compound72 or 109 of the present invention was suspended in a 5% gum arabicsolution (physiological saline) and administered orally twice daily indose of 60 mg/kg or 90 mg/kg body weight for 10 days. On the day whenthe dosing was ended, the diameters of tumors were measured. Tumorvolume was calculated by the following formula: volume of tumor=longestdiameter×shortest diameter×shortest diameter×½. The growth rate oftumors was obtained as the proportion of the gained tumor volume whichwas substracted the initial volume from the final volume in the treatedanimals to the gained tumor volume which was substracted the initialvolume from the final volume in the control animals. The body weights ofmice administered with compounds of the present invention were measuredduring the experiment to observe no decrease.

The results are shown in [Table 9].

TABLE 9 Inhibition of athymic nude mice implanted cancer growth DoseTumor growth Compound (mg/kg/day) rate (%)  72 120 84 180 71 109 120 35

Compounds of the present invention inhibited dose-dependently the growthof human breast cancer implanted to athymic nude mice.

Test Example 10 In vivo Inhibition of Prostate Cancer (1)

5,000,000 cells of human prostatic cancer cell line, LNCaP, weresuspended in a gelmatrix solution and implanted subcutaneously at thebreast in 8-week old male Balb/C-strain athymic nude mice (Friedman R.et al., Proceedings of the National Academy of Sciences of the U.S.A.Vol. 87, pp.6698-6702, 1990). 42 days (in the case of compound 72) or 57days (in the case of compound 109) after the implantation, the diametersof tumors were measured. Five mice per group with similar tumor sizewere used for the experiment. Compounds 72 or 109 of the presentinvention was suspended in a 5% gum arabic solution (physiologicalsaline) and administered orally twice daily in a dose of 60 mg/kg and 90mg/kg body weight for 10 days. After the completion of the dosing, thediameters of tumor were measured. The tumor volume was calculated by thefollowing formula: volume of tumor=longest diameter×shortestdiameter×shortest diameter×½. The growth rate of tumors was obtained asthe proportion of the gained tumor volume which was subtracted theinitial volume from the final volume in the treated animals to thegained tumor volume which was subtracted the initial volume from thefinal volume in the control animals. The body weights of miceadministered with compounds of the present invention were measuredduring the experiment to observe no decrease.

The results are shown in [Table 10].

TABLE 10 Inhibition of athymic nude mice implanted cancer growth DoseTumor growth Compound (mg/kg/day) rate (%)  72  0 100 120  91 180  57109  0 100 120  28

Compounds 72 and 109 of the present invention have the effect ofinhibiting tumor growth of hormone dependent prostate cancer LNCaP.

Test Example 11 In vivo Inhibition of Prostate Cancer (2)

5,000,000 cells of human prostate cancer cell line, LNCaP, weresuspended in a gelmatrix solution and implanted subcutaneously at thebreast in 8-week old male Balb/C-strain athymic nude mice (Friedman R.et al., Proceedings of the National Academy of Sciences of the U.S.A.Vol. 87, pp.6698-6702, 1990). 33 days after the implantation, thediameters of tumors were measured. Five mice per group with similartumor size were used for the experiment. Compound 8 of the presentinvention was suspended in a 5% gum arabic solution (physiologicalsaline) and administered orally twice daily in a dose of 30 mg/kg bodyweight for 21 days. For another experiment, the mice were castrated 33days after implantation of the cancer cell for observing the effect ofhormone depletion on the prostate cancer growth. Furthermore, Compound 8of the present invention was administered orally twice daily in a doseof 30 mg/kg body weight for 21 days to the castrated mice. After thecompletion of the dosing, the diameters of tumor were measured. Thetumor volume was calculated by the following formula: volume oftumor=longest diameter×shortest diameter×shortest diameter×½. The growthrate of tumors was obtained as the proportion to the volume of tumor inthe control animals in which only the gum arabic solution wasadministered. The body weights of mice administered with Compound 8 ofthe present invention were measured during the experiment to observe nodecrease.

The results are shown in [Table 11].

TABLE 11 Inhibition of athymic nude mice implanted cancer growthConcentration of Tumor growth compound (mg/kg/day) rate (%)  0 100  6080  0 69 (castrated group) 60 55 (castrated group)

Compound 8 of the present invention has the effect of inhibiting tumorgrowth of hormone dependent prostate cancer LNCaP. The tumor growthinhibiting effect of this compound was found to be further enhanced whenthe hormone levels were reduced by castration. Testectomy is widelypracticed for treatment of patients with prostatic cancer. Also, hormonetherapy such as treatment with an LH-RH antagonist is now practiced forthe treatment. Therefore, the compounds of the present invention mayoffer a more effective therapeutic method for treatment of prostaticcancer by combination with these conventional therapeutic methods.

Formulation Example 1 (Dosage Per Tablet)

(1) Compound of Working Example 8 10.0 mg (2) Lactose 60.0 mg (3) Cornstarch 35.0 mg (4) Gelatin  3.0 mg (5) Magnesium stearate  2.0 mg

A mixture of 10.0 mg of the compound of Working Example 8, 60.0 mg oflactose and 35.0 mg of corn starch was granulated, by using 0.03 ml of a10 weight % aqueous solution of gelatin (3.0 mg. in terms of gelatin),through a sieve of 1 mm mesh. The granules were dried at 40° C., whichwere again subjected to sieving. The resulting granules were mixed with2.0 mg of magnesium stearate, which was compressed. Thus-obtained coretablets was sugar-coated with a suspension consisting of sucrose,titanium dioxide, talc and gum arabica, followed by polishing with beewax.

Formulation Example 2 (Dosage Per Tablet)

(1) Compound of Working Example 8 10.0 mg (2) Lactose 70.0 mg (3) Cornstarch 50.0 mg (4) Soluble starch  7.0 mg (5) Magnesium stearate  3.0 mg

A mixture of 10.0 mg of the compound of Working Example 8 and 3.0 mg ofmagnesium stearate was granulated by using 0.07 ml of an aqueoussolution of soluble starch (7.0 mg in terms of soluble starch) anddried, which was mixed with 70.0 mg of lactose and 50.0 mg of cornstarch. The mixture was compressed to give a tablet.

Reference Example 1

To a suspension of lithium aluminum hydride (350 mg) in diethyl ether(10 ml) was added dropwise, at 0° C., a solution of ethyl4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyrate (3.00 g)in diethyl ether (10 ml)—tetrahydrofuran (10 ml). The mixture wasstirred at 0° C. for one hour and at room temperature for further onehour, followed by addition of water. The mixture was acidified with 2Nhydrochloric acid and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with ethyl acetate-hexane(1:1,v/v),4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butanol (2.00 g,74%) was obtained. Recrystallization from ethyl acetate-hexane affordedcolorless needles, mp 90-91° C.

Reference Example 2

In substantially the same manner as in Reference Example 1, ethyl3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propionate wasreduced to give 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol. The yield was 94%. Recrystallization from ethyl acetate-hexanegave colorless needles, mp 95-96° C.

Reference Example 3

In substantially the same manner as in Reference Example 1, methyl4-[2-((E)-2-phenylethenyl]-4-oxazolylmethoxy]phenylacetate was reducedto give 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol.The yield was 50%. Recrystallization from acetone-isopropyl ether gavecolorless prisms, mp 123-124° C.

Reference Example 4

In substantially the same manner as in Reference Example 1, ethyl5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentanoate wasreduced to give5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentanol. Theyield was 68%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 93-94° C.

Reference Example 5

In substantially the same manner as in Reference Example 1, ethyl6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexanoate wasreduced to give6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexanol. Theyield was 60%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 94-95° C.

Reference Example 6

In substantially the same manner as in Reference Example 1, ethyl3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]phenyl]propionate wassubjected to reduction to give3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol. Theyield was 82%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 57-58° C.

Reference Example 7

In substantially the same manner as in Reference Example 1, ethyl3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propionate wasreduced to give3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol. Theyield was 33%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 76-77° C.

Reference Example 8

In substantially the same manner as in Reference Example 1, ethyl3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propionatewas reduced to give3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol.The yield was 68%. Recrystallization from ethyl acetate-hexane gavecolorless needles, mp 95-96° C.

Reference Example 9

In substantially the same manner as in Reference Example 1, ethyl3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propionatewas reduced to give3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol.The yield was 60%. Recrystallization from ethyl acetate-hexane gavecolorless needles, mp 126-128° C.

Reference Example 10

In substantially the same manner as in Reference Example 1, ethyl4-[4-benzyloxyphenyl)butyrate was reduced to give 4-(4-benzyloxyphenyl)butanol. The yield was 87%. Recrystallization from isopropyl ether gavecolorless leaflets, mp 59-60° C.

Reference Example 11

In substantially the same manner as in Reference Example 1, ethyl3-(4-benzyloxyphenyl)propionate was reduced to give3-(4-benzyloxyphenyl) propanol. The yield was 95%. Recrystallizationfrom ethyl acetate-hexane gave colorless prisms, mp 63-64° C.

Reference Example 12

To a mixture of4-[4-[2-(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butanol (1.74 g),triethylamine (660 mg) and ethyl acetate (50 ml) was added, at 0° C.,methanesulfonyl chloride (745 mg). The mixture was stirred for two hoursat room temperature. To the reaction mixture were supplementedtriethylamine (350 mg) and methanesulfonyl chloride (405 mg). Themixture was stirred at room temperature overnight. The reaction mixturewas poured into water and extracted with ethyl acetate. The ethylacetate layer was washed successively with saturated aqueous sodiumhydrogencarbonate, 1N hydrochloric acid and brine, dried (MgSO₄), andconcentrated under reduced pressure to give4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butylmethanesulfonate (2.00 g, 94%). Recrystallization from ethylacetate-hexane gave colorless prisms, mp 82-83° C.

Reference Example 13

In substantially the same manner as in Reference Example 12,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol wasallowed to react with methanesulfonyl chloride to give3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate. The yield was 92%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 111-112° C.

Reference Example 14

In substantially the same manner as in Reference Example 12,2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol wasallowed to react with methanesulfonyl chloride to give2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethylmethanesulfonate. The yield was 82%. Recrystallization fromacetone-isopropyl ether gave colorless prisms, mp 121-122° C.

Reference Example 15

In substantially the same manner as in Reference Example 12,5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentanol wasallowed to react with methanesulfonyl chloride to give5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentylmethanesulfonate. The yield was 96%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 105-106° C.

Reference Example 16

In substantially the same manner as in Reference Example 12,6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]phenyl]hexanol wasallowed to react with methanesulfonyl chloride to give6-[4-[2-[(E)-2-phenyl ethenyl]-4-oxazolylmethoxy]phenyl]hexylmethanesulfonate. The yield was 97%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 88-89° C.

Reference Example 17

In substantially the same manner as in Reference Example 12,3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol wasallowed to react with methanesulfonyl chloride to give3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate. The yield was 78%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 75-76° C.

Reference Example 18

In substantially the same manner as in Reference Example 12,3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol wasallowed to react with methanesulfonyl chloride to give3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate. The yield was 95%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 93-94° C.

Reference Example 19

In substantially the same manner as in Reference Example 12,3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanolwas allowed to react with methanesulfonyl chloride to give3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate. The yield was 99%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 130-131° C.

Reference Example 20

In substantially the same manner as in Reference Example 12,3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanolwas allowed to react with methanesulfonyl chloride to give3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate. The yield was 94%. Recrystallization from ethylacetate-hexane gave pale yellow needles, mp 112-113° C.

Reference Example 21

In substantially the same manner as in Reference Example 12,3-(4-benzyloxyphenyl)propanol was allowed to react with methanesulfonylchloride to give 3-(4-benzyloxyphenyl)propyl methanesulfonate. The yieldwas 98%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 74-75° C.

Reference Example 22

A mixture of3-[4-methoxy-3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate (900 mg), sodium iodide (3.00 g) and acetone (20 ml)was heated for one hour under reflux. The reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried (MgSO₄), and concentrated under reducedpressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with ethyl acetate-hexane (1:4,v/v),4-[3-(3-iodopropyl)-2-methoxyphenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole(905 mg, 95%) was obtained. Recrystallization from ethyl acetate-hexanegave colorless needles, mp 103-104° C.

Reference Example 23

A mixture of 4-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]benzaldehyde(5.00 g), sodium borohydride (620 mg), tetrahydrofuran (50 ml) andethanol (50 ml) was stirred for 16 hours at room temperature. Thereaction mixture was poured into water and acidified with 2Nhydrochloric acid. The resulting precipitate was collected by filtrationand dried, which was suspended in chloroform (50 ml). To the suspensionwas added thionyl chloride (2.00 g). The mixture was stirred for onehour at room temperature. The reaction mixture was concentrated, towhich was added ethyl acetate, followed by washing with saturatedaqueous sodium hydrogencarbonate and water. The ethyl acetate layer wasseparated and dried (MgSO₄). The solvent was distilled off to leavecrystals, followed by recrystallization from chloroform-isopropyl etherto give 4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole(3.25 g, 61%) as colorless prisms, mp 116-117° C.

Reference Example 24

A solution of aluminum chloride (7.07 g) in diethyl ether (90 ml) wasadded dropwise, at 0° C., to a suspension of lithium aluminum hydride(7.59 g) in diethyl ether (300 ml). The mixture was stirred for 15minutes, to which was added dropwise, at 0° C., a solution of ethyl4-benzyloxy-3-methoxycinnamate (50,0 g) in diethyl ether (250 ml). Themixture was stirred for one hour at room temperature, to which was addedwater (200 ml), then, was carefully added 5N sulfuric acid (280 ml) at0° C. The diethyl ether layer was taken. The aqueous layer was extractedwith ethyl acetate. Organic layers were combined, washed with water,dried (MgSO₄), and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography. From the fractioneluted with ethyl acetate-hexane (3:2, v/v),3-(4-benzyloxy-3-methoxyphenyl)-2-propen-1-ol (34.2 g, 79%) wasobtained. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 81-82° C.

Reference Example 25

To a solution of 4-(4-benzyloxyphenyl)butanol (3.55 g), tributylphosphine (6.84 g) and 1,2,4-triazole (1.86 g) in tetrahydrofuran (75ml) was added dropwise, at room temperature, diethyl azodicarboxylate(40% toluene solution, 11.8 g). The mixture was heated for two hoursunder reflux. The reaction mixture was poured into water and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography. From the fractioneluted with ethyl acetate-hexane (1:2, v/v),1-[4-(4-benzyloxyphenyl)butyl]-1,2,4-triazole (3.45 g, 83%) wasobtained. Recrystallization from isopropyl ether gave colorless prisms,mp 68-69° C.

Reference Example 26

In substantially the same manner as in Reference Example 25,3-(4-benzyloxy-3-methoxyphenyl)-2-propen-1-ol was allowed to react with1,2,4-triazole to give1-[3-(4-benzyloxy-3-methoxyphenyl)-2-propenyl]-1,2,4-triazole. The yieldwas 34%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 70-72° C.

Reference Example 27

A mixture of 3-(4-benzyloxyphenyl)propyl methanesulfonate (55.0 g),imidazole (17.6 g), potassium carbonate (35.7 g) andN,N-dimethylformamide (500 ml) was stirred for 6 hours at 80° C. Thereaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), andconcentrated under reduced pressure to give1-[3-(4-benzyloxyphenyl)propyl]imidazole (34.7 g, 69%).Recrystallization from ethyl acetate-hexane gave colorless needles, mp80-81° C.

Reference Example 28

A mixture of 1-[4-(4-benzyloxyphenyl)butyl]-1,2,4-triazole (3.15 g),palladium-carbon (5%, 3.0 g) and ethanol (50 ml) was subjected tocatalytic hydrogenation under atmospheric pressure at room temperature.The catalyst was filtered off, and the filtrate was concentrated. Theresidue was subjected to a silica gel column chromatography. Thecrystalline product obtained from the fraction eluted withtetrahydrofuran-hexane (1:1, v/v) was recrystallized from ethylacetate-hexane to give 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (1.22g, 55%) as colorless prisms, mp 135-136° C.

Reference Example 29

In substantially the same manner as in Reference Example 28,1-[3-(4-benzyloxy-3-methoxyphenyl)-2-propenyl]-1,2,4-triazole wassubjected to catalytic hydrogenation to give1-[3-(4-hydroxy-3-methoxyphenyl)propyl]-1,2,4-triazole. The yield was78%. Recrystallization from ethyl acetate-hexane gave colorless prisms,mp 97-98° C.

Reference Example 30

In substantially the same manner as in Reference Example 28,1-[3-(4-benzyloxyphenyl)propyl]imidazole was subjected to catalytichydrogenation to give 1-[3-(4-hydroxyphenyl)propyl]imidazole. The yieldwas 81%. Recrystallization from ethanol gave colorless prisms, mp158-160° C.

Reference Example 31

A mixture of cinnamamide (25.3 g) and 1,3-dichloroacetone (20.9 g) wasstirred for one hour at 130° C. The reaction mixture was diluted withwater, neutralized with potassium carbonate, and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and concentrated under reduced pressure. The residue was subjected to asilica gel column chromatography. From the fraction eluted with diethylether-hexane, 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole (16.9 g,47%) was obtained. Recrystallization from diethyl ether-hexane gavecolorless needles, mp 72-73° C.

Reference Example 32

In substantially the same manner as in Reference Example 31,3,4-dihydro-2-naphthalenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole. The yield was 60%.Recrystallization from isopropyl ether gave colorless prisms, mp 73-74°C.

Reference Example 33

In substantially the same manner as in Reference Example 31,phenylacetamide was allowed to react with 1,3-dichloroacetone to give2-benzyl-4-chloromethyl oxazole. The yield was 33%. Recrystallizationfrom hexane gave colorless prisms, mp 31-32° C.

Reference Example 34

In substantially the same manner as in Reference Example 31,isobutyramide was allowed to react with 1,3-dichloroacetone to give4-chloromethyl-2-isopropyl oxazole as an oily product. The yield was6.2%.

NMR (δ ppm in CDCl₃): 1.35(6H,d,J=7 Hz), 3.0-3.15(1H,m), 4.50(2H,s),7.55(1H,s).

Reference Example 35

In substantially the same manner as in Reference Example 31,4-chlorobenzamide was allowed to react with 1,3-dichloroacetone to give4-chloromethyl-2-(4-chlorophenyl)oxazole. The yield was 54%.Recrystallization from isopropyl ether gave colorless needles, mp 97-98°C.

Reference Example 36

In substantially the same manner as in Reference Example 31,4-benzyloxybenzamide was allowed to react with 1,3-dichloroacetone togive 2-(4-benzyloxyphenyl)-4-chloromethyloxazole. The yield was 33%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp119-120° C.

Reference Example 37

In substantially the same manner as in Reference Example 31,3-benzyloxybenzamide was allowed to react with 1,3-dichloroacetone togive 2-(3-benzyloxyphenyl)-4-chloromethyloxazole. The yield was 26%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp49-50° C.

Reference Example 38

In substantially the same manner as in Reference Example 31,3,5-dimethoxybenzamide was allowed to react with 1,3-dichloroacetone togive 4-chloromethyl-2-(3,5-dimethoxyphenyl)oxazole. The yield was 59%.Recrystallization from ethyl acetate-hexane gave colorless needles, mp85-86° C.

Reference Example 39

In substantially the same manner as in Reference Example 31,3,5-dimethylbenzamide was allowed to react with 1,3-dichloroacetone togive 4-chloromethyl-2-(3,5-dimethylphenyl)oxazole. The yield was 52%.Recrystallization from isopropyl ether gave colorless needles, mp 76-77°C.

Reference Example 40

In substantially the same manner as in Reference Example 31,4-cyanobenzamide was allowed to react with 1,3-dichloroacetone to give4-chloromethyl-2-(4-cyanophenyl)oxazole. The yield was 41%.Recrystallization form ethyl acetate-hexane gave colorless prisms, mp134-135° C.

Reference Example 41

In substantially the same manner as in Reference Example 31,cyclohexanecarboxamide was allowed to react with 1,3-dichloroacetone togive 4-chloromethyl-2-cyclohexyloxazole as an oily product. The yieldwas 2.7%.

NMR (δ ppm in CDCl₃): 1.2-1.9(8H,m), 2.0-2.15(2H,m), 2.6-2.95(1H,m),4.49(2H,s), 7.54(1H,s).

Reference Example 42

A mixture of thiocinnamamide (11.7 g), 1,3-dichloroacetone (9.10 g) andethanol (145 ml) was heated for one hour under reflux. The reactionmixture was poured onto ice-water, neutralized with potassium carbonate,and extracted with ethyl acetate. The ethyl acetate layer was washedwith water, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with diethyl ether-hexane (1:5, v/v),4-chloromethyl-2-[(E)-2-phenylethenyl]thiazole (9.40 g, 66%) wasobtained. Recrystallization from diethyl ether-hexane gave colorlessplates, mp 88-89° C.

Reference Example 43

In substantially the same manner as in Reference Example 31,2-naphthalenecarboxamide was allowed to react with 1,3-dichloroacetoneto give 4-chloromethyl-2-(2-naphthyl)oxazole. The yield was 68%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp116-117° C.

Reference Example 44

In substantially the same manner as in Reference Example 31,2-benzo[b]thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give 2-(2-benzo[b]thienyl)-4-chloromethyloxazole.The yield was 33%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 150-151° C.

Reference Example 45

In substantially the same manner as in Reference Example 31, ethylsuccinamidate was allowed to react with 1,3-dichloroacetone to giveethyl 4-chloromethyl-2-oxazolepropionate as an oily product. The yieldwas 7.2%.

NMR (δ ppm in CDCl₃): 1.26(3H,t,J=7 Hz), 2.81(2H,t,J=7.5 Hz),3.09(2H,t,J=7.5 Hz), 4.19(2H,q,J=7 Hz), 4.48(2H,s), 7.56(1H,s).

Reference Example 46

In substantially the same manner as in Reference Example 31,3,3-diphenylpropenamide was allowed to react with 1,3-dichloroacetone togive 2-(2,2-diphenylethenyl)-4-chloromethyloxazole. The yield was 49%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp107-108° C.

Reference Example 47

A mixture of 2-thiophenecarboxamide (5.09 g) and 1,3-dichloroacetone(457 g) was stirred at 120° C. for 2 hours. The reaction mixture waspoured into water, nautralized with potassium carbonate, and thenextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with diethyl ether-hexane (1:9, v/v),4-chloromethyl-2-(2-thienyl)oxazole (4.09 g, 57%) was obtained.Recrystallization from isopropylether gave colorless needles, mp 59-59°C.

Reference Example 48

In substantially the same manner as in Reference Example 47, crotonamidewas allowed to react with 1,3-dichloroacetone to give4-chloromethyl-2-(1-propenyl)oxazole. The yield is 10%. Oily substance.

NMR(δ ppm in CDCl₃): 1.94(3H,dd,J=6.6,1.6 Hz), 4.50(2H,s),6.29(1H,dd,J=15.8,1.6 Hz), 6.76(1H,dq,J=15.8,6.6 Hz), 7.53(1H,s).

Reference Example 49

In substantially the same manner as in Reference Example 47,3-cyclohexylpropeneamide was allowed to react with 1,3-dichloroacetoneto give 4-chloromethyl-2-[(E)-2-cyclohexylethenyl]oxazole. The yield was4.5%. Oily substance.

NMR (δ ppm in CDCl₃): 1.05-1.4(5H,m), 1.65-1.9(5H,m), 2.05-2.3(1H,m),4.49(2H,s), 6.23(1H,d,J=16.2 Hz), 6.70(1H,dd,J=16.2,7 Hz), 7.53(1H,s).

Reference Example 50

In substantially the same manner as in Reference Example 47,4-benzoylbenzamide was allowed to react with 1,3-dichloroacetone to give2-(4-benzoylphenyl)-4-chloromethyloxazole. The yield was 46%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp138-139° C.

Reference Example 51

In substantially the same manner as in Reference Example 47,2-benzofurancarboxamide was allowed to react with 1,3-dichloroacetone togive 2-(2-benzofuranyl)-4-chloromethyloxazole. The yield was 30%.Recrystallization from ethyl acetate-hexane gave colorless needles, mp133-134° C.

Reference Example 52

In substantially the same manner as in Reference Example 47,9-fluorenone-2-carboxamide was allowed to react with 1,3-dichloroacetoneto give 4-chloromethyl-2-(9-fluorenone-2-yl)oxazole. The yield was 18%.Recrystallization from ethyl acetate-hexane was yellow prisms, mp188-189° C.

Reference Example 53

In substantially the same manner as in Reference Example 47,9-fluorenylideneacetamide was allowed to react with 1,3-dichloroacetoneto give 4-chloromethyl-2-(9-fluorenylidene)methyloxazole. The yield was36%. Recrystallization from ethyl acetate-hexane gave yellow prisms, mp175-176° C.

Reference Example 54

In substantially the same manner as in Reference Example 47,5-methyl-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(5-methyl-2-thienyl)oxazole. The yield was 46%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp84-85° C.

Reference Example 55

In substantially the same manner as in Reference Example 47,5-chloro-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(5-chloro-2-thienyl)oxazole. The yield was 51%.Recrystallization from ethyl acetate-hexane gave colorless needles, mp90-91° C.

Reference Example 56

In substantially the same manner as in Reference Example 47,3-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone togive 4-chloromethyl-2-(3-thienyl)oxazole. The yield was 50%.Recrystallization from ethyl acetate-hexane gave colorless needles, mp91-92° C.

Reference Example 57

In substantially the same manner as in Reference Example 47,2-furancarboxamide was aollowed to react with 1,3-dichloroacetone togive 4-chloromethyl-2-(2-furyl)oxazole. The yield was 47%. Oilysubstance.

NMR (δ ppm in CDCl₃): 4.56(2H,s), 6.54(1H,dd,J=3.5,1.8 Hz),7.06(1H,dd,J=3.5,0.6 Hz), 7.55-7.6(2H,m).

Reference Example 58

In substantially the same manner as in Reference Example 47,2-phenyl-5-benzoxazolecarboxamide was allowed to react with1,3-dichloroacetone to give5-(4-chloromethyl-2-oxazolyl)-2-phenylbenzoxazole. The yield was 65%.Recrystallization from ethyl acetate-hexane gave brown needles, mp194-195° C.

Reference Example 59

In substantially the same manner as in Reference Example 47,3-methyl-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(3-methyl-2-thienyl)oxazole. The yield was 61%.Recrystallization from ethyl acetate-hexane gave colorless needles, mp95-96° C.

Reference Example 60

In substantially the same manner as in Reference Example 47,5-ethyl-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give 4-chloromethyl-2-(5-ethyl-2-thienyl)oxazole.The yield was 54%.

NMR (δ ppm in CDCl₃): 1.34(3H,t,J=7.6 Hz), 2.89(2H,qd,J=7.6,1 Hz),4.54(2H,d,J=0.8 Hz), 6.80(1H,dt,J=3.8,1 Hz), 7.51(1H,d,J=3.8 Hz),7.61(1H,t,J=0.8 Hz).

Reference Example 61

In substantially the same manner as in Reference Example 47,4,5,6,7-tetrahydro-2-benzothiophene carboxamide was allowed to reactwith 1,3-dichloroacetone to give4-chloromethyl-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole. The yieldwas 53%. Recrystallization from ethyl acetate-hexane gave colorlessneedles, mp 102-103° C.

Reference Example 62

In substantially the same manner as in Reference Example 47,5-bromo-4-methyl-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole. The yield was 53%.Recrystallization from ethyl acetate-hexane gave clolorless prisms, mp71-72° C.

Reference Example 63

In substantially the same manner as in Reference Example 47,5-chloro-2-furancarboxamide was allowed to react with1,3-dichloroacetone to give 2-(5-chloro-2-furyl)-4-chloromethyloxazole.The yield was 24%. Recrystallization from diethyl ether-hexane gavecolorless prisms, mp 107-108° C.

Reference Example 64

In substantially the same manner as in Reference Example 47,5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetoneto give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%.Recrystallization from diethyl ether-hexane gave colorless needles, mp90-92° C.

Reference Example 65

In substantially the same manner as in Reference Example 47,5-methyl-2-furancarboxamide was allowed to react with1,3-dichloroacetone to give 4-chloromethyl-2-(5-methyl-2-furyl)oxazole.The yield was 38%. Recrystallization from diethyl ether-hexane gave.Colorless needles, mp 93-94° C.

Reference Example 66

In substantially the same manner as in Reference Example 47,3-chloro-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(3-chloro-2-thienyl)oxazole. The yield was 54%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp84-85° C.

Reference Example 67

In substantially the same manner as in Reference Example 47,4-chloro-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(4-chloro-2-thienyl)oxazole. The yield was 48%.Recrystallization from diethyl ether-hexane gave colorless needles, mp72-73° C.

Reference Example 68

In substantially the same manner as in Reference Example 47,5-methoxy-2-thiophenecarboxamide was allowed to react with1,3-dichloroacetone to give4-chloromethyl-2-(5-methoxy-2-thienyl)oxazole. The yield was 1.2%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp64-65° C.

Reference Example 69

A mixture of 2-amino-4-phenylphenol (5.00 g), chloroacetylchloride (3.35g), triethylamine (3.00 g), pyridinium tosylate (2.24 g) and xylene (100ml) was heated under reflux for 15 hours. To the reaction mixture wasadded ethyl acetate, washed with water, dried (MgSO₄), and concentratedunder reduced pressure. The residue was subjected to a silica gelchromatography. From the fraction eluted with the ethyl acetate-hexane(1:9, v/v), crystals of 2-chloromethyl-5-phenylbenzoxazole (2.01 g, 31%)was obtained. Recrystallization from ethyl acetate-hexane gave yellowneedles, mp 96-97° C.

Reference Example 70

A mixture of 2-amino-5-bromopyridine (10.0 g). 1,3-dichloroacetone (7.71g) and 1,2-dimethoxyethane (40 ml) was stirred at room temperature for 4hours. The precipitated crystals were collected by filtration, to whichethanol (100 ml) was added and heated under reflux. The reaction mixturewas concentrated, diluted with saturated aqueous sodium bicarbonate, andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated under reduced pressure to givecrystals of 6-bromo-2-chloromethylimidazo-[1,2-a]pyridine (1.48 g, 10%).Recrystallization from ethyl acetate-hexane gave colorless needles, mp129-130° C.

Reference Example 71

To a solution of methyl 3-amino-4-hydroxybenzoate and triethylamine(2.42 g) in tetrahydrofuran (60 ml) was added dropwise a solution of2-thiophenecarbonyl chloride (3.50 g) in tetrahydrofuran (40 ml) at 0°C. The resultant was stirred at room temperature for 2 hours. Thereaction mixture was poured into water, and extracted with ethylacetate. The ethyl acetate layer was washed with 1N-hydrochloric acidand water, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with chloroform-methanol (100:1, v/v), the crystals ofmethyl 3-(2-thiophenecarboxamide)-4-hydroxybenzoate (2.24 g, 34%) wasobtained. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 241-242° C. A mixture methyl of3-(2-thiophenecarboxamide)-4-hydroxybenzoate ester (2.20 g), phosphoruspentoxide (4.49 g), hexamethyldisiloxane (10.3 g) and1,2-dichlorobenzene (30 ml) was heated for 3 hours under reflux. Thereaction mixture was poured into water, and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and concentrated under reduced pressure. The residue was subjected to asilica gel column chromatography. From the fraction eluted with ethylacetate-hexane (1:4, v/v), methyl 2-(2-thienyl)-5-benzoxazolcarboxylate(1.70 g, 83%) was obtained. Recrystallization from ethyl acetate-hexanegave colorless prisms, mp 141-142° C.

Reference Example 72

To a solution of methyl 2-(2-thienyl)-5-benzoxazolecarboxylate (1.50 g)in tetrahydrofuran (30 ml) was slowly added lithium aluminum hydride(220 mg) at 0° C., stirred for 30 minutes. To the reaction mixture wasadded water, which was made acidic with 1N-hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (4:1, v/v),2-(2-thienyl)-5-benzoxazolyl methanol (1.03 g, 77%) was obtained. Therecrystalization from ethyl acetate-hexane gave colorless needles, mp158-159° C.

Reference Example 73

To 2-(2-thienyl)-5-benzoxazolylmethanol (600 mg) was added thionylchloride (3 ml) at 0° C., stirred for 3 hours. The reaction mixture wasconcentrated, which was neutalized with saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The ethyl acetate layerwas washed with water, dried (MgSO₄), and concentrated under reducedpressure to give crystals of 5-chloromethyl-2-(2-thienyl) benzoxazole(550 mg, 85%). The recrystalization from ethyl acetate-hexane gavecolorless needles, mp 152-153° C.

Reference Example 74

A mixture of 2-thiophenecarboxamide (10.2 g), Lawesson's reagent (16.2g) and toluene (150 ml) was heated for 1 hour under reflux. The reactionmixture was concentrated, to which were added ethyl bromopyruvate (15.7g) and ethanol (100 ml) and stirred for 1.5 hours at 50° C. To thereaction mixture was add water, which was neutralized with saturatedaqueous sodium bicarbonate, and extracted with ethyl acetate. The ethylacetate layer was washed with water, dried (MgSo₄), and concentratedunder reduced pressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with ethyl acetate-hexane (1:4,v/v), ethyl 2-(2-thienyl)-4-thiazolecarboxylate (14.6 g, 76%) wasobtained. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 72-73° C.

Reference Example 75

In substantially the same manner as in Reference Example 72, ethyl2-(2-thienyl)-4-thiazolecarboxylate was reduced with lithium aluminumhydride to give crystals of 2-(2-thienyl)-4-thiazolylmethanol. The yieldwas 94%. Recrystallization from ethyl acetate-hexane gave colorlessneedles, mp 54-55° C.

Reference Example 76

In substantially the same manner as in Reference Example 73,2-(2-thienyl)-4-thiazolylmethanol was allowed to react withthionylchloride to give 4-chloromethyl-2-(2-thienyl)thiazole. The yieldwas 65%. Recrystallization from ethyl acetate-hexane gave colorlessneedles, mp 54-55° C.

Reference Example 77

A mixture of 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole (5.0 g),sodium acetate (7.48 g) and N,N-dimethylformamide (50 ml) was stirred at90° C. for 4.5 hours. The reaction mixture was poured onto ice-water,and extracted with ethyl acetate. The ethyl acetate layer was washedwith water dried (MgSO₄), and concentrated under reduced pressure. Tothe residue was added potassium carbonate (4.73 g), water (25 ml) andmethanol (50 ml) and then the resultant was stirred for 2 hours at roomtemperature. The reaction mixture was concentrated, to which was addedbrine, and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried (MgSO₄), and concentrated under reducedpressure to give 2-[(E)-2-phenylethenyl]-4-oxazolylmethanol (4.18 g,91%). Recrystallization from ethyl acetate-hexane gave colorless prisms,mp 94-95° C.

Reference Example 78

In substantially the same manner as in Reference Example 77,4-chloromethyl-2-(2-thienyl)oxazole was allowed to react with sodiumacetate, and then hydrolyzed to give 2-(2-thienyl)oxazolylmethanol. Theyield was 80%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 98-99° C.

Reference Example 79

To a solution of 3-(4-mercaptophenyl)propionic acid (2.0 g) andtriethylamine (2.23 g) in N,N-dimethylformamide (50 ml) was addeddropwise a solution of 4-chloromethyl-2-[(E)-2-phenyl ethenyl]oxazole(2.20 g) in N,N-dimethylformamide (10 ml) at 0° C. and then stirred for2.5 hours. To the reaction mixture was added water, and extracted withdiethyl ether. The water layer was made acidic with concentratedhydrochloric acid, and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and concentrated underreduced pressure to give crystals of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionic acid (3.05 g, 84%).Recrystallization from ethyl acetate-hexane gave colorless prisms, mp120-121° C.

Reference Example 80

To a mixture of3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionic acid(365 mg) and ethanol (10 ml) was added concentrated sulfuric acid (onedrop) and heated for 4 hours under reflux. The reaction mixture wasconcentrated, to which was added saturated aqueous sodium bicarbonate,and extracted with ethyl acetate. The ethyl acetate layer was washedwith water, dried (MgSO₄), and concentrated under reduced pressure togive crystals of ethyl3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionate(310 mg, 80%). Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 77-78° C.

Reference Example 81

To a solution of ethyl3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionate(205 mg) in tetrahydrofuran (10 ml) was added lithium aluminum hydrideat 0° C. and then stirred for one hour at room temperature. To thereaction mixture were added water and 1N-hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated under reduced pressure to givecrystals of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propanol (135 mg, 77%).Recrystallization from ethyl acetate-hexane gave colorless needles, mp91-92° C.

Reference Example 82

A solution of ethyl 3-benzyloxycinnamate in tetrahydrofuran (300 ml) wasadded dropwise to a suspension of lithium aluminum hydride intetrahydrofuran (300 ml) at 0° C. and then stirred for 2 hours. To thereaction mixture was added carefully water and the insoluble materialwas filtered off. The filtrate was concentrated. The residue wasdissolved in ethyl acetate and washed with 1N-hydrochloric acid andwater, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (1:4, v/v),3-(3-benzyloxyphenyl)propanol (52.7 g, 62%) was obtained. Oilysubstance.

NMR (δ ppm in CDCl₃): 1.8-1.95(2H,m), 2.68(2H,t,J=6.8 Hz);3.65(2H,t,J=6.6 Hz), 5.05(2H,s), 6.75-6.85(3H,m), 7.15-7.5(6H,m).

Reference Example 83

A solution of 4-(3-benzyloxyphenyl)butyric acid (22.0 g) intetrahydrofuran (150 ml) was added dropwise to a suspension of lithiumaluminum hydride (6.18 g) in tetrahydrofuran (150 ml) at 0° C. and thenstirred for one hour at room temperature. The reaction mixture wasquenched with H₂O, acidified with 1N-hydrochloric acid, and extractedwith ethyl acetate. The ethyl acetate layer was washed with1N-hydrochloric acid, saturated aqueous sodium bicarbonate and water,dried (MgSO₄), and concentrated under reduced pressure to give4-(3-benzyloxyphenyl)butanol (20.5 g, 99%). Oily substance.

NMR (δ ppm in CDCl₃): 1.5-1.8(4H,m), 2.62(2H,t,J=7.4 Hz),3.64(2H,t,J=6.4 Hz), 5.05(2H,s), 6.75-6.85(3H,m), 7.15-7.45(6H,m).

Reference Example 84

Methanesulfonyl chloride (320 mg) was added to a solution of3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propanol (500mg) and triethylamine (280 mg) in tetrahydrofuran (30 ml) at 0° C. andthen stirred for 4 hours at room temperature. To the reaction mixturewas added water, and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and concentrated underreduced pressure to give3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propylmethanesulfonate (540 mg, 90%). Recrystallization from ethylacetate-hexane gave pale yellow prisms, mp 97-98° C.

Reference Example 85

Methanesulfonyl chloride (17.9 g) was added to a solution of4-(4-benzyloxyphenyl)butanol (20.0 g) and triethyl amine (15.8 g) inethyl acetate (500 ml) at 0° C. and then stirred for 5 hours at roomtemperature. The reaction mixture was washed with water, dried (MgSo₄)and concentrated under reduced pressure to give4-(4-benzyloxyphenyl)butyl methanesulfonate (26.0 g, quantitatively).Oily substance.

NMR(δ ppm in CDCl₃): 1.6-1.85(4H,m), 2.60(2H,t,J=7 Hz), 2.97(3H,s),4.22(2H,t,J=6 Hz), 5.04(2H,s), 6.90(2H,d,J=8.6 Hz), 7.08(2H,d,J=8.6 Hz),7.3-7.45(5H,m).

Reference Example 86

In substantially the same manner as in Reference Example 85,3-(3-benzyloxyphenyl)propanol was allowed to react with methanesulfonylchloride to give 3-(3-benzyloxyphenyl)propyl methanesulfonate. The yieldwas quantative. Oily substance.

NMR(δ ppm in CDCl₃): 2.0-2.15(2H,m), 2.73(2H,t,J=7.6 Hz), 2.98(3H,s),4.22(2H,t,J=6.2 Hz), 5.06(2H,s), 6.75-6.85(3H,m), 7.15-7.5(6H,m).

Reference Example 87

In substantially the same manner as in Reference Example 85,4-(3-benzyloxyphenyl)butanol was allowed to react withmethanesulfonylchloride to give 4-(3-benzyloxyphenyl)butylmethanesulfonate. The yield was quantative. Oily substance.

NMR(δ ppm in CDCl₃): 1.7-1.8(4H,m), 2.64(2H,t,J=7 Hz), 2.98(3H,s),4.22(2H,t,J=6 Hz), 5.06(2H,s), 6.75-6.85(3H,m), 7.21(1H,dd,J=9.2,7.2Hz), 7.3-7.5(5H,m).

Reference Example 88

A mixture of 4-(4-benzyloxyphenyl)butyl methane sulfonate (25.0 g),imidazole (11.2 g), potassium carbonate (15.5 g) andN,N-dimethylformamide (200 ml) was stirred for 16 hours at 80° C. Thereaction mixture was poured into water, and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and concentrated under reduced pressure. The residue was subjected to asilica gel column chromatography. From the fraction eluted with ethylacetate-methanol (20:1, v/v), 1-[4-(4-benzyloxyphenyl)butyl]imidazole(14.0 g, 61%) was obtained. Recrystallization from ethyl acetate-hexanegave colorless prisms, mp 97-98° C.

Reference Example 89

In substantially the same manner as in Reference Example 88,3-(3-benzyloxyphenyl)propyl methanesulfonate was allowed to react withimidazole to give 1-[3-(3-benzyloxyphenyl)propyl]imidazole. The yieldwas 44%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 82-83° C.

Reference Example 90

In substantially the same manner as in Reference Example 88,4-(3-benzyloxyphenyl)butyl methanesulfonate was allowed to react withimidazole to give 1-[4-(3-benzyloxyphenyl)butyl]imidazole. The yield was61%. Oily substance.

NMR(δ ppm in CDCl₃): 1.5-1.8(4H,m), 2.58(2H,t,J=7.2 Hz), 3.88(2H,t,J=7Hz), 5.03(2H,s), 6.7-6.85(4H,m), 7.04(1H,s), 7.15-7.5(7H,m).

Reference Example 91

A mixture of 1-[4-(4-benzyloxyphenyl)butyl]imidazole (13.0 g),palladium-carbon (5%, 10.0 g) and ethanol (100 ml) was subjected tocatalitic hydrogenation at room temperature under 1 atom. The catalystwas filtered off, and the filtrate was concentrated to give1-[4-(4-hydroxyphenyl)butyl]imidazole (8.58 g, 94%). Recrystallizationfrom ethyl acetate-hexane gave colorless prisms, mp 124-125° C.

Reference Example 92

In substantially the same manner as in Reference Example 91,1-[3-(3-benzyloxyphenyl)propyl]imidazole was subjected to catalitichydrogenation to give 1-[3-(3-hydroxyphenyl)propyl]imidazole. The yieldwas 90%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 110-111° C.

Reference Example 93

In substantially the same manner as in Reference Example 91,1-[4-(3-benzyloxyphenyl)butyl]imidazole was subjected to catalitichydrogenation to give 1-[4-(3-hydroxyphenyl)butyl]imidazole. The yieldwas 80%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 133-134° C.

Reference Example 94

To a mixture of 5-amino-2-methoxypyridine (5.00 g), 47% hydrobromic acid(8.75 g) and acetone (50 ml) was added dropwise a solution of sodiumnitrite (3.06 g) in water (5 ml) at 5-10° C. After stirring for 30minutes, methyl acrylate (20.8 g) was added, to which cuprous oxide (50mg) was added while stirring vigorously at 15° C. After stirring for onehour at room temperature, the reaction mixture was concentrated,concentrated aqueous ammonia was added, and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and concentrated under reduce pressure. The residue was subjected to asilica gel chromatography. From the fraction eluted with ethylacetate-hexane (1:9, v/v), methyl2-bromo-3-(2-methoxy-5-pyridyl)propionate (6.40 g, 58%) was obtained.Oily substance.

NMR(δ ppm in CDCl₃): 3.18(1H,dd,J=14.6,7.6 Hz), 3.42(1H,dd,J=14.6,7.6Hz), 3.75(3H,s), 3.92(3H,s), 4.33(1H,t,J=7.6 Hz), 6.70(1H,d,J=8.6 Hz),7.44(1H,dd,J=8.6,2.4 Hz), 8.02(1H,d,J=2.4 Hz).

The oily substance (6.30 g) was dissolved in methanol (150 ml), andsubjected to catalytic hydrogenation on palladium-carbon (5%, 4.0 g).The catalyst was filtered off and the filtrate was concentrated. To theresidue was added saturated aqueous sodium bicarbonate, and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and concentrated under reduced pressure to give methyl3-(2-methoxy-5-pyridyl)propionate (3.68 g, 82%). Oily substance.

NMR(δ ppm in CDCl₃): 2.59(2H,t,J=7.6 Hz), 2.88(2H,t,7.6 Hz), 3.67(3H,s),3.91(3H,s), 6.68(1H,d,J=8.4 Hz), 7.42(1H,dd,J=8.4,2.4 Hz),8.00(1H,d,J=2.4 Hz).

Reference Example 95

In substantially the same manner as in Reference Example 82, methyl3-(2-methoxy-5-pyridyl)propionate was reduced by lithium aluminumhydride to give 3-(2-methoxy-5-pyridyl)propanol. The yield wasquantative. Oily substance.

NMR(δ ppm in CDCl₃): 1.8-2.0(2H,m), 2.64(2H,t,J=7.6 Hz), 3.6-3.75(2H,m),3.91(3H,s), 6.69(1H,d,J=8.4 Hz), 7.43(1H,dd,J=8.4,2.6 Hz),7.99(1H,d,J=2.6 Hz).

Reference Example 96

In substantially the same manner as in Reference Example 85,3-(2-methoxy-5-pyridyl)propanol was reacted with methanesulfonylchloride to give 3-(2-methoxy-5-pyridyl)propyl methanesulfonate. Theyield was quantative. Oily substance.

NMR(δ ppm in CDCl₃): 1.95-2.1(2H,m), 2.68(2H,t,J=7.4 Hz), 3.01(3H,s),3.91(3H,s), 4.23(2H,t,J=7.4 Hz), 6.70(1H,d,J=7.8 Hz),7.41(1H,dd,J=7.8,1.2 Hz), 7.98(1H,d,J=1.2 Hz).

Reference Example 97

In substantially the same manner as in Reference Example 88,3-(2-methoxy-5-pyridyl)propyl methanesulfonate was reacted withimidazole to give 5-[3-(1-imidazolyl)propyl]-2-methoxypyridine. Theyield was 94%. Oily substance.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.54(2H,t,J=7.5 Hz), 3.9-4.0(5H,m),6.70(1H,d,J=8.4 Hz), 6.92(1H,s), 7.08(1H,s), 7.3-7.4(1H,m), 7.47(1H,s),7.96(1H,s).

Reference Example 98

A mixture of 5-[3-(1-imidazolyl)propyl]-2-methoxypyridine(2.10 g),phosphorus oxychloride (7.44 g) and N,N-dimethylformamide (14.6 g) wasstirred at 100° C. for 10 hours. To the reaction mixture was addedsaturated aqueous sodium acetate and saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The ethyl acetate layerwas washed with water, dried (MgSO₄), and concentrated under reducedpressure. The residue was subjected to a silica gel chloromatography.From the fraction eluted with ethyl acetate-methanol (20:1, v/v),2-chloro-5-[3-(1-imidazolyl)propyl]pyridine (1.28 g, 60%) was obtained.Oily substance.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.60(2H,t,J=7.9 Hz), 3.99(2H,t,J=7Hz), 6.91(1H,s), 7.09(1H,s), 7.25-7.3(1H,m), 7.4-7.5(2H,m),8.21(1H,d,J=2.4 Hz).

Reference Example 99

In substantially the same manner as in Reference Example 47,3-furancarboxamide was reacted with 1,3-dichloroacetone to give4-chloromethyl-2-(3-furyl)oxazole. The yield was 44%. Recrystallizationfrom diethyl ether-hexane gave colorless prisms. mp 70-71° C.

Reference Example 100

In substantially the same manner as in Reference Example 47,2-thiopheneacetamide was reacted with 1,3-dichloroacetone to give4-chloromethyl-2-(2-thienylmethyl)oxazole. The yield was 27%. Oilysubstance.

NMR(δ ppm in CDCl₃): 4.32(2H,s), 4.49(2H,s), 6.95-7.0(2H,m),7.15-7.25(1H,m), 7.58(1H,s).

Reference Example 101

In substantially the same manner as in Reference Example 77, ethyl2-(1-pyrrolyl)-4-thiazolecarboxylate was reduced by lithium aluminumhydride to give 2-(1-pyrrolyl)-4-thiazolylmethanol. The yield was 69%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp111-113° C.

Reference Example 102

In substantially the same manner as in Reference Example 77, ethyl2-(3-pyridyl)-4-thiazolecarboxylate was reduced by lithium aluminumhydride to give 2-(3-pyridyl)-4-thiazolylmethanol. The yield was 16%.Recrystallization from ethyl acetate-hexane gave colorless needles, mp121-122° C.

Reference Example 103

In substantially the same manner as in Reference Example 47,5-cyano-2-thiophenecarboxamide was reacted with 1,3-dichloroacetone toobtain 4-chloromethyl-2-(5-cyano-2-thienyl)oxazole. The yield was 22%.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp146-147° C.

Reference Example 104

A mixture of 2-thiophenecarboxamide (15.2 g) and ethyl4-chloroacetoacetate (19.6 g) was stirred at 130° C. for 4 h. Water,ethyl acetate and potassium carbonate were added to the reactionmixture. The ethyl acetate layer was separated, washed with water, dried(MgSO₄), and concentrated. The residue was purified by silica gel columnchromatography. From the fraction eluted with diethyl ether-hexane (1:9,v/v) ethyl 2-(2-thienyl)-4-oxazolylacetate (1.48 g, 5%) was obtained.Recrystallization from hexane gave colorless prisms, mp 56-57° C.

Reference Example 105

Sodium hydride (60% in oil, 1.20 g) was added to a stirred solution ofdiethyl malonate (6.01 g) in N,N-dimethylformamide (40 ml) at roomtemperature. After stirring for 30 min, a solution of4-chloromethyl-2-(2-thienyl)oxazole (5.0 g) in N,N-dimethylformamide (20ml) was added dropwise to the mixture, and then the stirring wascontinued for 5 h. The reaction mixture was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated. The residue was dissolved inacetic acid (100 ml) and 6N HCl (40 ml). After refluxing for 5 h, thereaction mixture was concentrated. The residue was made alkaline withaqueous sodium hydroxide and extracted with diethyl ether. The aqueouslayer was separated, acidified with conc.HCl and extracted with ethylacetate. The ethyl acetate layer was washed with brine, dried (MgSO₄),and concentrated. Ethanol (200 ml) and conc.H₂SO₄ (0.5 ml) were added tothe residue, and then the resultant was refluxed for 9 h. The reactionmixture was concentrated and diluted with ethyl acetate. The ethylacetate layer was washed with saturated aqueous sodium bicarbonate andwater, dried (MgSO₄), and concentrated to give an oil which was purifiedby silica gel column chromatography. From the fraction eluted with ethylacetate-hexane (1:9, v/v) ethyl 3-[2-(2-thienyl)-4-oxazolyl]propionate(1.81 g, 29%) was obtained. Recrystallization from hexane gave colorlessprisms, mp 42-43° C.

Reference Example 106

In substantially the same manner as in Reference Example 72. ethyl2-(2-thienyl)-4-oxazolylacetate was subjected to reduction with lithiumalminum hydride to obtain 2-[2-(2-thienyl)-4-oxazolyl]ethanol as an oil.The yield was 73%.

NMR(δ ppm in CDCl₃): 2.82(2H,td,J=6,1 Hz), 3.94(2H,t,J=6 Hz),7.11(1H,dd,J=5,3.6 Hz), 7.42(1H,dd,J=5,1.2 Hz), 7.46(1H,t,J=1Hz),7.65(1H,dd,J=3.6,1.2 Hz).

Reference Example 107

In substantially the same manner as in Reference Example 72, ethyl3-[2-(2-thienyl)-4-oxazolyl]propionate was subjected to reduction withlithium alminum hydride to obtain 3-[2-(2-thienyl)-4-oxazolyl]propanolas an oil. The yield was 97%.

NMR(δ ppm in CDCl₃): 1.8-2.2(2H,m), 2.70(2H,t,J=7 Hz), 3.75(2H,td,J=6,1Hz), 7.05-7.15(1H,m), 7.35-7.45(2H,m), 7.6-7.7(1H,m).

Reference Example 108

A mixture of 2-bromoacetylthiophene (4.10 g), ethyl thiooxamate (2.93 g)and ethanol (40 ml) was refluxed for 4 h. The reaction mixture waspoured into water and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and concentrated to give anoil which was purified by silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (1:5, v/v) ethyl4-(2-thienyl)-2-thiazolecarboxylate was obtained. Recrystallization fromisopropyl ether gave pale yellow prisms (1.37 g, 29%), mp 50-52° C.

Reference Example 109

2-bromoacetylthiophene (10.3 g) was added to a stirred solution ofhexamethylenetetramine (7.71 g) in chloroform (60 ml), and stirred atroom temperature for 3 h. The precipitated2-thiophenecarbonylmethylhexaminium bromide (15.9 g, 92%) was collectedby filtration. The cryst. (10.4 g) was added to a mixture of ethanol(100 ml) and conc.HCl (24 ml), and then stirred at 50° C. for 1 h. Thereaction mixture was cooled and the insoluble crystals were removed byfiltration. The filtrate was concentrated to give crystals which werecollected by filtration. The cryst. (1.80 g) was added to a mixture ofethyl chloroglyoxylate (1.34 ml) and toluene (20 ml), and then stirredat 80° C. for 6 h. The reaction mixture was poured into wate andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated aqueous sodium bicarbonate and water, dried (MgSO₄), andconcentrated to give an oil which was purified by silica gel columnchromatography. From the fraction eluted with ethyl acetate-hexane (1:1,v/v) the crystals of ethyl N-(2-thiophenecarbonylmethyl)oxamate (1.24 g,51%) were obtained. The cryst. (1.11 g) and diphosphorus pentasulfide(2.05 g) were suspended in chloroform (20 ml) and refluxed for 3 h. Thereaction mixture was diluted with water and the insoluble material wasremoved by filtration. The chloroform layer was separated, washed withwater, dried (MgSO₄), and concentrated to obtain ethyl5-(2-thienyl)-2-thiazolecarboxylate (1.07 g, 97%). Recrystallizationfrom ethyl acetate-hexane gave colorless needles, mp 68-69° C.

Reference Example 110

Acetic acid (3.78 ml) was added to a stirred mixture of2-thiophenecarbothioamide (3.15 g), ethyl chloroformylacetate potassiumsalt (6.23 g) and ethanol (60 ml). Afte refluxing for 4 h, ethylchloroformylacetate potassium salt (4.15 g) and acetic acid (2.52 ml)were added, and then the refluxing was continued for further 20 h. Thereaction mixture was concentrated, diluted with saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The ethyl acetate layerwas washed with water, dried (MgSO₄), and concentrated to give an oilwhich was purified by silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (1:1, v/v) the crystals ofethyl 2-(2-thienyl)-5-thiazolecarboxylate (3.29 g, 63%) were obtained.Recrystallization from ethyl acetate-hexane gave colorless needles, mp61-62° C.

Reference Example 111

Methanol (1.5 ml) in tetrahydrofuran (2 ml) was added dropwise to astirred and refluxed mixture of ethyl4-(2-thienyl)-2-thiazolecarboxylate (1.36 g), sodium borohydride (0.35g) and tetrahydrofuran (15 ml). After refluxing for 1 h, the reactionmixture was poured into water, acidified with 1N HCl and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and concentrated to give 4-(2-thienyl)-2-thiazolylmethanol(0.92 g, 82%). Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 113-114° C.

Reference Example 112

In substantially the same manner as in Reference Example 111, ethyl5-(2-thienyl)-2-thiazolecarboxylate was subjected to reduction withsodium borohydride to obtain 5-(2-thienyl)-2-thiazolylmethanol. Theyield was 74%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 67-68° C.

Reference Example 113

In substantially the same manner as in Reference Example 111, ethyl2-(2-thienyl)-5-thiazolecarboxylate was subjected to reduction withsodium borohydride to obtain 2-(2-thienyl)-5-thiazolylmethanol. Theyield was 94%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 89-90° C.

Reference Example 114

A mixture of 5-methyl-2-thiophenecarboxamide (0.79 g),1,3-dichloroacetone (0.63 g), and ethanol (20 ml) was refluxed for 2 h.The reaction mixture was concentrated, diluted with saturated aqueoussodium bicarbonate, and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and concentrated. Theresidue was purified by silica gel column chromatography. From thefraction eluted with diethyl ether-hexane (1:10, v/v)4-chloromethyl-2-(5-methyl-2-thienyl)thiazole (0.60 g, 52%) wasobtained. Recrystallization from diethyl ether-hexane gave colorlessprisms, mp 89-90° C.

Reference Example 115

A mixture of 2-thiophenecarbonylmethylhexaminium bromide (10.4 g),ethanol (100 ml) and conc.HCl (24 ml) was stirred at 50° C. for 1 h. Thereaction mixture was cooled and the insoluble crystals were removed byfiltration. The filtrate was concentrated to give crystals (5.20 g,quant.) which were collected by filtration. The cryst. (3.55 g) wasadded to a mixture of toluene (20 ml) and water (20 ml), and thenchloroacetyl chloride (1.43 ml) and 2N sodium hydroxide (10 ml) wereadded dropwise to the mixture at 0° C. After stirring at roomtemperature for 2 h, the crystals were collected by filtration. Thetoluene layer was separated, washed with water, dried (MgSO₄), andconcentrated to give crystals. The crystals combined were recrystallizedfrom ethyl acetate to give N-(2-thiophenecarbonylmethyl)chloroacetamide(1.82 g, 42%). A mixture of the cryst. (1.67 g), toluene (20 ml) andphosphorus oxychloride (1.8 ml) was stirred at 80° C. for 4H. Thereaction mixture was concentrated, diluted with water, neutralized withpotassium carbonate, and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and concentrated. Theresidue was purified by silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (1:3, v/v)2-chloromethyl-5-(2-thienyl)oxazole (1.40 g, 92%) was obtained as anoil.

NMR(δ ppm in CDCl₃): 4.65(2H,s), 7.09(1H,dd,J=5,3.8 Hz), 7.18(1H,s),7.3-7.4(2H,m).

Reference Example 116

A mixture of ethyl 7-methoxy-3-quinolinecarboxylate (12.0 g) and 47% HBr(200 ml) was refluxed for 24 h. The precipitated crystals (12.63 g) werecollected and added to a mixture of ethanol (400 ml) and conc.H₂SO₄ (2ml). After refluxing for 20 h, the reaction mixture was concentrated,diluted with saturated aqueous sodium bicarbonate, and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and concentrated to give ethyl7-hydroxy-3-quinoline-carboxylate (5.70 g, 51%). Recrystallization fromethyl acetate-hexane gave colorless prisms, 179-180° C.

Reference Example 117

Sodium hydride (60% in oil, 1.07 g) was added to a stirred solution ofethyl 7-hydroxy-3-quinolinecarboxylate (5.30 g) in tetrahydrofuran (200ml) at 0° C., and stirred at room temperature for 1 h.N-phenyltrifluoromethanesulfonimide (10.47 g) was added to the mixture,and the resultant was stirred for 1 h. The reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried (MgSO₄), and concentrated. The residue waspurified by silica gel column chromatography. From the fraction elutedwith ethyl acetate-hexane (1:4, v/v) ethyl7-trifluoromethanesulfonyloxy-3-quinolinecarboxylate (7.65 g, 90%) wasobtained. Recrystallization from ethyl acetate-hexane gave colorlessprisms, 153-154° C.

Reference Example 118

A solution of phenylboronic acid (2.48 g) in ethanol (30 ml) was addeddropwise to a stirred mixture of ethyl7-trifluoromethanesulfonyloxy-3-quinolinecarboxylate (7.40 g), 2N sodiumcarbonate (28 ml), lithium chloride (2.70 g),tetrakis(triphenylphosphine)palladium (1.27 g) and toluene (120 ml)under argon atmospher. After stirring at 90° C. for 14 h, the insolublematerial was removed by filtration. The filtrate was extgracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium bicarbonate and water, dried (MgSO₄), and concentrated. Theresidue was purified by silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (1:4, v/v) ethyl7-phenyl-3-quinolinecarboxylate (5.14 g, 87%) was obtained.Recrystallization from ethyl acetate-hexane gave colorless prisms,118-119° C.

Reference Example 119

In substantially the same manner as in Reference Example 118,7-trifluoromethanesulfonyloxy-3-quinolinecarboxylate was reacted with2-thienylboronic acid to obtain ethyl7-(2-thienyl)-3-quinolinecarboxylate. The yield was 67%.Recrystallization from ethyl acetate-hexane gave colorless prisms,146-147° C.

Reference Example 120

In substantially the same manner as in Reference Example 72,7-phenyl-3-quinolinecarboxylate was subjected to reduction with lithiumaluminum hydride to obtain 7-phenyl-3-quinolylmethanol. The yield was39%. Recrystallization from ethyl acetate-hexane gave colorless prisms,128-129° C.

Reference Example 121

Diisobutylalminium hydride (1M in toluene, 7.2 ml) was added dropwise toa stirred solution of 7-(2-thienyl)-3-quinolinecarboxylate (500 mg) intetrahydrofuran (30 m) at 0° C. After stirring for 30 min, the reactionmixture was poured into water and extracted with ethyl acetate. Theethyl acetate layer was washed with brine, dried (MgSO₄), andconcentrated. The residue was purified by silica gel columnchromatography. From the fraction eluted with ethyl acetate-hexane (1:2,v/v) 7-(2-thienyl)-3-quinolylmethanol (270 mg, 63%) was obtained.Recrystallization from ethyl acetate-hexane gave yellow prisms, 143-144°C.

Reference Example 122

In substantially the same manner as in Reference Example 73,7-phenyl-3-quinolylmethanol was reacted with thionyl chloride to obtain3-chloromethyl-7-phenylquinoline. The yield was 96%. Recrystallizationfrom ethyl acetate-hexane gave colorless prisms, 105-106° C.

Reference Example 123

In substantially the same manner as in Reference Example 73,7-(2-thienyl)-3-quinolylmethanol was reacted with thionyl chloride toobtain 3-chloromethyl-7-(2-thienyl)quinoline. The yield was 77%.Recrystallization from ethyl acetate-hexane gave colorless leaflets,120-121° C.

Reference Example 124

In substantially the same manner as in Reference Example 82, ethyl4-benzyloxy-3-methoxycinnamate was subjected to reduction with lithiumaluminum hydride to obtain 3-(4-benzyloxy-3-methoxyphenyl)propanol. Theyield was 56%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, 57-58° C.

Reference Example 125

In substantially the same manner as in Reference Example 85,3-(4-benzyloxy-3-methoxyphenyl)propanol was reacted with methanesulfonylchlorode to obtain 3-(4-benzyloxy-3-methoxyphenyl)propylmethanesulfonate. The yield was quantitative. Recrystallization fromethyl acetate-hexane gave colorless prisms, 87-88° C.

Reference Example 126

In substantially the same manner as in Reference Example 88,3-(4-benzyloxy-3-methoxyphenyl)propyl methanesulfonate was reacted withimidazole to obtain 1-[3-(4-benzyloxy-3-methoxyphenyl)propyl]imidazoleas an oil. The yield was 57%.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.55(2H,t,J=7.4 Hz), 3.88(3H,s),3.92(2H,t,J=7 Hz), 5.13(2H,s), 6.6-6.7(3H,m), 6.82(1H,d,J=8 Hz),6.9-7.5(8H,m).

Reference Example 127

In substantially the same manner as in Reference Example 91,1-[3-(4-benzyloxy-3-methoxyphenyl)propyl]imidazole was subjected tocatalytic hydrogenation to obtain1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole. The yield was 83%.Recrystallization from ethyl acetate gave colorless prisms, 127-128° C.

Reference Example 128

In substantially the same manner as in Reference Example 82, ethyl3-(3-chloro-4-methoxymethoxyphenyl)propionate was subjected to reductionwith lithium aluminum hydride to obtain3-(3-chloro-4-methoxymethoxyphenyl)propanol as an oil. The yield was97%.

NMR(δ ppm in CDCl₃): 1.8-1.95(2H,m), 2.64(2H,t,J=7.6 Hz), 3.52(3H,s),3.66(2H,t,J=6.2 Hz), 5.22(2H,s), 6.95-7.25(3H,m).

Reference Example 129

In substantially the same manner as in Reference Example 85,3-(3-chloro-4-methoxymethoxyphenyl)propanol was reacted withmethanesulfonyl chloride to obtain3-(3-chloro-4-methoxymethoxyphenyl)propyl methanesulfonate as an oil.The yield was quantitative.

NMR(δ ppm in CDCl₃): 1.95-2.15(2H,m), 2.96(2H,t,J=7.5 Hz), 3.00(3H,s),3.52(3H,s), 4.22(2H,t,J=6.4 Hz), 5.22(2H,s), 6.95-7.15(2H,m),7.2-7.25(1H,m).

Reference Example 130

In substantially the same manner as in Reference Example 88,3-(3-chloro-4-methoxymethoxyphenyl)propyl methanesulfonate was reactedwith imidazole to obtain1-[3-(3-chloro-4-methoxymethoxyphenyl)propyl]imidazole as an oil. Theyield was 65%.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.54(2H,t,J=7.7 Hz), 3.52(3H,s),3.93(2H,t,J=7 Hz), 5.22(2H,s), 6.9-7.0(3H,m), 7.05-7.2(3H,m),7.46(1H,s).

Reference Example 131

A mixture of 1-[3-(3-chloro-4-methoxymethoxyphenyl)propyl]imidazole(4.50 g), 10% H₂SO₄ (50 ml) and acetone (50 ml) was refluxed for 3 h.Sodium hydroxide (7.0 g) was added to the mixture at 0° C., andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated to obtain1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole (3.50 g, 92%).Recrystallization from ethanol gave colorless prisms, 112-113° C.

Reference Example 132

A mixture of 2-cyanothiophene (10.9 g), hydroxylamine hydrochloride(6.96 g), and 70% ethanol (100 ml) was stirred at 80° C. for 2 h. Thereaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate layer was extracted with 2N HCl. The aqueous layercombined was made alkaline with potassium carbonate and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and concentrated to give crystals (12.4 g, 87%). The crystals(7.11 g) was mixed with potassium carbonate in acetone, and thenchloroacetyl chloride was added ropwise to the mixture at 0° C. Afterstirring at room temperature for 16 h, the reaction mixture wasconcentrated and treated with water to give crystals (8.82 g, 81%) whichwere collected by filtration. The crystals (7.82 g) was added to xylene(100 ml), and then refluxed with separating wate for 2 h. The reactionmixture was concentrated and diluted with ethyl acetate. The ethylacetate layer was washed with water, dried (MgSO₄), and concentrated.The residue was purified by silica gel column chromatography. From thefraction eluted with ethyl acetate-hexane (1:10, v/v) crystals of5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole were obtained.Recrystallization from ethyl acetate-hexane gave colorless prisms (6.23g, 87%), mp 58-59° C.

Working Example 1

To a solution of3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol (760mg), tributyl phosphine (1.01 g) and 1,2,4-triazole (280 mg) intetrahydrofuran (15 ml) was added dropwise, at 0° C., diethylazodicarboxylate (700 mg). The mixture was heated for one hour underreflux, poured into water, and extracted with ethyl acetate. The ethylacetate layer was washed with water, dried (MgSO₄), and concentrated.The residue was subjected to a silica gel column chromatography. Thecrystals obtained from the fraction eluted with ethyl acetate-hexane(2:1, v/v) were recrystallized from ethyl acetate-hexane to give1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole(540 mg, 70%) as colorless prisms, mp 108-109° C.

Working Example 2

In substantially the same manner as in Working Example 1,4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butanol wasallowed to react with 1,2,4-triazole to give1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole.The yield was 71%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 94-95° C.

Working Example 3

In substantially the same manner as in Working Example 1,5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentanol wasallowed to react with 1,2,4-triazole to give1-[5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentyl]-1,2,4-triazole.The yield was 60%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 103-104° C.

Working Example 4

In substantially the same manner as in Working Example 1,3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol wasallowed to react with 1,2,4-triazole to give1-[3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole.The yield was 61%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 59-60° C.

Working Example 5

In substantially the same manner as in Working Example 1,3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol wasallowed to react with 1,2,4-triazole to give1-[3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole.The yield was 54%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 72-73° C.

Working Example 6

In substantially the same manner as in Working Example 1,6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexanol wasallowed to react with 1,2,4-triazole to give1-[6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexyl]-1,2,4-triazole.The yield was 65%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 90-91° C.

Working Example 7

In substantially the same manner as in Working Example 1,2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol wasallowed to react with 1,2,4-triazole to give1-[2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl]-1,2,4-triazole.The yield was 75%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 136-137° C.

Working Example 8

To a solution of imidazole (70 mg) in N,N-dimethylformamide (5 ml) wasadded, at 0° C., sodium hydride (60%, in oil, 50 mg). The mixture wasstirred for one hour. To the reaction mixture was added3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate (350 mg). The mixture was stirred for 1.5 hour at 70°C. The reaction mixture was diluted with water and extracted with ethylacetate. The ethyl acetate layer was washed with water, dried (MgSO₄),and concentrated. The resulting crystalline product was recrystallizedfrom ethyl acetate-hexane to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole(200 mg, 61%) as colorless prisms, mp 127-128° C.

Working Example 9

In substantially the same manner as in Working Example 8, imidazole wasallowed to react with4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-methanesulfonateto give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 61%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 103-104° C.

Working Example 10

In substantially the same manner as in Working Example 8, 1,2,3-triazolewas allowed to react with4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butylmethanesulfonate. The extracted mixture was subjected to a silica gelcolumn chromatography. From the fraction eluted with ethylacetate-hexane (2:3, v/v),2-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-2H-1,2,3-triazole.The yield was 35%. Recrystallization from ethyl acetate-hexane gavecolorless leaflets, mp 90-91° C.

Working Example 11

In the column chromatography in Working Example 10, from the fractionsubsequently eluted with ethyl acetate-hexane (2:1, v.v),1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-1H-1,2,3-triazolewas obtained. The yield was 25%. Recrystallization from ethylacetate-hexane gave colorless needles, mp 125-126° C.

Working Example 12

In substantially the same manner as in Working Example 8, 1,2,3-triazolewas allowed to react with3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate. The reaction mixture was subjected to a silica gelcolumn chromatography. From the fraction eluted with ethylacetate-hexane (1:1, v/v),2-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2H-1,2,3-triazolewas obtained. The yield was 35%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 103-104° C.

Working Example 13

In the column chromatography in Working Example 12, from the fractioneluted subsequently,1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1H-1,2,3-triazolewas obtained. The yield was 22%. Recrystallization from ethyl acetategave colorless needles, mp 142-143° C.

Working Example 14

In substantially the same manner as in Working Example 8, pyrazole wasallowed to react with3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate to give2-[(E)-2-phenylethenyl]-4-[4-3-(1-pyrazolyl)propyl]phenoxymethyl]oxazole.The yield was 67%. Recrystallization from isopropyl ether gave colorlessleaflets, mp 94-95° C.

Working Example 15

In substantially the same manner as in Working Example 8,2-methylimidazole was allowed to react with3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate to give4-[4-[3-(2-methyl-1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 47%. Recrystallization form ethyl acetate-hexane gavecolorless prisms, mp 93-94° C.

Working Example 16

In substantially the same manner as in Working Example 8, imidazole wasallowed to react with3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate to give4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 60%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, m,p.95-96° C.

Working Example 17

In substantially the same manner as in Working Example 8, imidazole wasallowed to react with5-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]pentylmethanesulfonate to give4-[4-[5-(1-imidazolyl)pentyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 66%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 101-102° C.

Working Example 18

In substantially the same manner as in Working Example 8, imidazole wasallowed to react with3-[3-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate to give4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 63%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 86-87° C.

Working Example 19

In substantially the same manner as in Working Example 8, imidazole wasallowed to react with3-[2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate to give4-[2-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazoleas an oily product. The yield was 80%.

NMR (δ ppm in CDCl₃): 2.12(2H,quint,J=7.4 Hz), 2.66(2H,t,J=7.4 Hz),3.94(2H,t,J=7.4 Hz), 5.04(2H,s), 6.9-7.58(16H,m).

Working Example 20

In substantially the same manner as in Working Example 8, imidazole wasallowed to react with 6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexyl methanesulfonate togive4-[4-[6-(1-imidazolyl)hexyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 66%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 108-109° C.

Working Example 21

In substantially the same manner as in Working Example 8, benzimidazolewas allowed to react with4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butylmethanesulfonate to give1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]benzimidazole.The yield was 36%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 148-149° C.

Working Example 22

In substantially the same manner as in Working Example 8,2-methylimidazole was allowed to react with4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butylmethanesulfonate to give4-[4-[4-(2-methyl-1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 42%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 122-123° C.

Working Example 23

In substantially the same manner as in Working Example 8,2-phenylimidazole was allowed to react with4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butylmethanesulfonate to give2-[(E)-2-phenylethenyl]-4-[4-[4-(2-phenyl-1-imidazolyl)butyl]phenoxymethyl]oxazole. The yield was 40%. Recrystallization fromethyl acetate-isopropyl ether gave colorless prisms, mp 85-86° C.

Working Example 24

In substantially the same manner as in Working Example 8, pyrrole wasallowed to react with3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethansulfonate to give2-[(E)-2-phenylethenyl]-4-[4-[3-(1-pyrrolyl)propyl]phenoxymethyl]oxazole.The yield was 57%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 108-109° C.

Working Example 25

A mixture of4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butylmethanesulfonate (430 mg), ethyl 2-imidazolecarboxylate (155 mg),potassium carbonate (305 mg) and N,N-dimethylformamide (10 ml) wasstirred for two hours at temperatures ranging from 80 to 90° C. Thereaction mixture was poured into water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), andconcentrated. The residue was subjected to a silica gel columnchromatography. The crystalline product obtained from the fractioneluted with ethyl acetate-hexane (2:1, v/v) was recrystallized fromethyl acetate-hexane to give ethyl1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-2-imidazolecarboxylate(280 mg, 60%) as colorless prisms, mp 96-97° C.

Working Example 26

In substantially the same manner as in Working Example 25,4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole wasallowed to react with imidazole to give4-[4-(1-imidazolylmethyl)phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.Recrystallization from ethyl acetate-hexane gave colorless prisms, mp149-150° C.

Working Example 27

In substantially the same manner as in Working Example 25,2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethylmethanesulfonate was allowed to react with imidazole to give4-[4-[2-(1-imidazolyl)ethyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 38%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 165-166° C.

Working Example 28

In substantially the same manner as in Working Example 25,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate was allowed to react with benzimidazole to give1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]benzimidazole.The yield was 49%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 115-117° C.

Working Example 29

In substantially the same manner as in Working Example 25,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate was allowed to react with ethyl 2-imidazolecarboxylateto give ethyl1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate.The yield was 68%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 123-124° C.

Working Example 30

In substantially the same manner as in Working Example 25,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate was allowed to react with dimethyl4,5-imidazoledicarboxylate to give dimethyl1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxylate.The yield was 63%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 85-86° C.

Working Example 31

In substantially the same manner as in Working Example 25,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate was allowed to react with 4,5-imidazoledicarboxamide togive1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxamide.The yield was 44%. Recrystallization from ethyl acetate gave colorlessprisms, mp 194-195° C.

Working Example 32

In substantially the same manner as in Working Example 25,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate was allowed to react with 4,5-diphenylimidazole to give4-[4-[3-(4,5-diphenyl-1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 53%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 137-138° C.

Working Example 33

A mixture of4-(4-chloromethylphenoxymethyl)-2-[(E)-2-phenylethenyl]oxazole (500 mg),1,2,4-triazole (160 mg), potassium carbonate (620 mg) andN,N-dimethylformamide (10 ml) was stirred for 2 hours at temperaturesranging from 80 to 90° C. The reaction mixture was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated. The residue was subjected to asilica gel column chromatography. From the fraction eluted with ethylacetate-methanol (20:1, v/v),1-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]benzyl]-1H-1,2,4-triazole(430 mg, 80%). Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 148-149° C.

Working Example 34

In the column chromatography in Working Example 33, from the fractionsubsequently eluted,4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]benzyl]-4H-1,2,4-triazole(40 mg, 7.4%) was obtained. Recrystallization from ethyl acetate gavecolorless prisms, mp 209-210° C.

Working Example 35

In substantially the same manner as in Working Example 33,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propylmethanesulfonate was allowed to react with tetrazole, and the reactionmixture was subjected to extraction. The extract was subjected to asilica gel column chromatography. From the fraction eluted with ethylacetate-hexane (1:1, v/v),2-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2H-tetrazolewas obtained. The yield was 41%. Recrystallization from ethylacetate-hexane gave colorless prisms, mp 97-98° C.

Working Example 36

In the column chromatography in Working Example 35, from the fractionsubsequently eluted,1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1H-tetrazolewas obtained. The yield was 23%. Recrystallization from ethyl acetategave colorless leaflets, mp 147-148° C.

Working Example 37

A mixture of 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (450 mg),4-chloromethyl-2-(3,4-dihydro-2-naphthyl) oxazole (565 mg), potassiumcarbonate (290 mg) and N,N-dimethylformamide (10 ml) was stirred for 6hours at 80° C. The reaction mixture was poured into water and extractedwith ethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and concentrated. The residue was subjected to a silica gelcolumn chromatography. A crystalline product obtained from the fractioneluted with chloroform-methanol (50:1, v/v) was recrystallized fromethyl acetate-hexane to give1-[4-[4-[2-(3,4-dihydro-2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazoleas colorless prisms, mp 96-97° C. The yield was 49%.

Working Example 38

In substantially the same manner as in Working Example 37,1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole was allowed to react with4-chloromethyl-5-methyl-2-(2-naphthyl)oxazole to give1-[4-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole.The yield was 54%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 134-135° C.

Working Example 39

In substantially the same manner as in Working Example 37,1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole was allowed to react with2-(2-benzofranyl)-4-chloromethyl-5-methyloxazole to give1-[4-[4-[2-(2-benzofranyl)-5-methyl-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole.The yield was 43%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 105-107° C.

Working Example 40

In substantially the same manner as in Working Example 37,1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole was allowed to react with2-(2-benzo[b]thienyl)-4-chloromethyl-5-methyloxazole to give1-[4-[4-[2-(2-benzo[b]thienyl)-5-methyl-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole.The yield was 59%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 131-132° C.

Working Example 41

In substantially the same manner as in Working Example 37,1-[3-(4-hydroxy-3-methoxyphenyl)propyl]-1,2,4-triazole was allowed toreact with 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give1-[3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole.The yield was 62%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 113-114° C.

Working Example 42

In substantially the same manner as in Working Example 37,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-phenyloxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenyloxazole. The yieldwas 42%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 111-112° C.

Working Example 43

In substantially the same manner as in Working Example 37,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole to give2-(3,4-dihydro-2-naphthyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 42%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 99-100° C.

Working Example 44

In substantially the same manner as in Working Example 37,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(2-benzo[b]thienyl)-4-chloromethyl-5-methyloxazole to give2-(2-benzo[b]thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyloxazole.The yield was 38%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 142-143° C.

Working Example 45

In substantially the same manner as in Working Example 37,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-benzyl-4-chloromethyloxazole to give2-benzyl-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yieldwas 23%. Recrystallization from ethyl acetate-isopropyl ether gavecolorless prisms, mp 61-62° C.

Working Example 46

In substantially the same manner as in Working Example 37,1-(4-hydroxyphenyl)imidazole was allowed to react with4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give4-[4-(1-imidazolyl)phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. Theyield was 68%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 160-162° C.

Working Example 47

Sodium hydride (90 mg) was added, at room temperature, to a solution of1-[3-(4-hydroxyphenyl)propyl]imidazole (405 mg) in N,N-dimethylformamide(10 ml). The mixture was stirred for 1.5 hour, to which was added4-chloromethyl-2-isopropyl oxazole (350 mg). The mixture was stirred forfurther 4 hours at 80° C. The reaction mixture was poured into water andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated. The residue was subjected to asilica gel column chromatography. From the fraction eluted with ethylacetate-hexane-methanol (20:10:1. v/v),4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-isopropyloxazole (450 mg,69%) as an oily product.

NMR(δ ppm in CDCl₃): 1.36(5H,d,J=6.8 Hz), 2.0-2.2(2H,m), 2.56(2H,t,J=7.5Hz), 3.0-3.2(1H,m), 3.92(2H,t,J=7 Hz), 4.96(2H,s), 6.9-7.0(3H,m),7.0-7.1(3H,m), 7.46(1H,s), 7.59(1H,s).

Working Example 48

Sodium hydride (440 mg) was added, at room temperature, to a solution of1-[3-(4-hydroxyphenyl)propyl]imidazole (2.02 g) in N,N-dimethylformamide(50 ml). The mixture was stirred for 1.5 hour, to which was added2-(4-benzyloxyphenyl)-4-chloromethyloxazole (3.60 g). The mixture wasstirred for further 3 hours at 80° C. The reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried (MgSO₄), and concentrated. The residue wassubjected to a silica gel column chromatography. A crystalline productobtained from the fraction eluted with ethyl acetate-methanol (50:1,v.v) was recrystallized from ethanol to give2-(4-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole(2.88 g, 62%) as colorless prisms, mp 133-134° C.

Working Example 49

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(4-chlorophenyl) oxazole to give2-(4-chlorophenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 76%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 116-117° C.

Working Example 50

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3,5-dimethoxyphenyl)oxazole to give2-(3,5-dimethoxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyloxazole.The yield was 76%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 59-60° C.

Working Example 51

In substantially the same manner as in Working example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3,5-dimethylphenyl)oxazole to give2-(3,5-dimethylphenyl)-4-[4-[3-(1-(imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 74%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 110-111° C.

Working Example 52

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(4-cyanophenyl) oxazole to give2-(4-cyanophenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 72%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 98-99° C.

Working Example 53

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(3-benzyloxyphenyl)-4-chloromethyloxazole to give2-(3-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 65%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 112-113° C.

Working Example 54

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-cyclohexyloxazole to give2-cyclohexyl-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. Theyield was 38%. Recrystallization from ether-hexane gave colorlessprisms, mp 46-47° C.

Working Example 55

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-5-methyl-2-[(E)-2-phenylethenyl]oxazole to give4-[4-[3-(1-imidazolyl)propyl)phenoxymethyl]-5-methyl-2-[(E)-2-phenylethenyl]oxazole.The yield was 66%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 94-95° C.

Working Example 56

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-[(E)-2-phenylethenyl]thiazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]thiazole.The yield was 58%. Recrystallization from ethyl acetate gave colorlessprisms, mp 129-130° C.

Working Example 57

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with5-chloromethyl-2-isopropyl benzoxazole to give5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-isopropyl-benzoxazole. Theyield was 59%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 76-77° C.

Working Example 58

A mixture of ethyl1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate(300 mg), 1N aqueous sodium hydroxide (1.32 ml) and tetrahydrofuran (3ml) was stirred for 2 hours at room temperature. To the reaction mixturewere added 1N hydrochloric acid (1.32 ml) and then water. The resultingcrystalline precipitate was collected by filtration and washed withether. Recrystallization from tetrahydrofuran gave1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]-phenyl]propyl]-2-imidazolecarboxylicacid (176 mg, 63%) as colorless prisms, mp 116° C. (decomp.).

Working Example 59

In substantially the same manner as in Working Example 58, dimethyl1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazole-dicarboxylatewas subjected to hydrolysis to give1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxylicacid. The yield was 26%. Recrystallization from acetone-methanol gavecolorless prisms, mp 216° C. (decomp.).

Working Example 60

To a suspension of lithium aluminum hydride (25 mg) in ether (5 ml) wasadded dropwise, under ice-cooling, a solution of ethyl1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate(300 mg) in ether (5 mg)—tetrahydrofuran (10 ml). The mixture wasstirred for one hour, to which was added 4N aqueous sodium hydroxide(0.025 ml). The mixture was stirred for 30 minutes at room temperature.The reaction mixture was poured into water, which was subjected toextraction with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated to leave a crystalline product.Recrystallization from ethyl acetate-hexane gave1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolyl-methoxy]phenyl]propyl]-2-imidazolemethanol(160 mg, 58%) as colorless prisms, mp 143-144° C.

Working Example 61

In substantially the same manner as in Working Example 60, dimethyl1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazole-dicarboxylatewas subjected to reduction to give1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledimethanol.The yield was 9%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 146-148° C.

Working Example 62

To a solution of4-[4-[3-(1-imidazolyl)propyl]-phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole(300 mg) in ethanol (100 ml) was added palladium-carbon (5%, wet, 300mg). The mixture was subjected to catalytic hydrogenation at roomtemperature under atmospheric pressure. The catalyst was filtered off.The filtrate was concentrated to leave a crystalline product, which wasrecrystallized from ethyl acetate-hexane to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-phenylethyl)oxazole(170 mg, 57%) as colorless prisms, mp 67-68° C.

Working Example 63

In substantially the same manner as in Working Example 62,2-(4-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolewas subjected to catalytic hydrogenation to give2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 60%. Recrystallization from ethanol gave colorless prisms,mp 182-183° C.

Working Example 64

In substantially the same manner as in Working Example 62,2-(3-benzyloxyphenyl)-4-[4-[3-1-imidazolyl)propyl]phenoxymethyl]oxazolewas subjected to catalytic hydrogenation to give2-(3-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 42%. Recrystallization from ethanol gave colorless prisms,mp 164-165° C.

Working Example 65

A mixture of2-(4-cyanophenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole(700 mg), sodium azide (585 mg), ammonium chloride (480 mg) andN,N-dimethylformamide (20 ml) was stirred for 24 hours at temperaturesranging from 130 to 135° C. The reaction mixture was poured into water,which was neutralized with 1N hydrochloric acid. The resultingcrystalline precipitate was collected by filtration. The filtrate wassubjected to extraction with ethyl acetate-tetrahydrofuran. The organiclayer was washed with water, dried (MgSO₄), and concentrated to leave acrystalline product. Both crystalline products were combined andrecrystallized from methanol to give5-[4-[4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolyl]phenyl]-1H-tetrazole(250 mg, 33%) as colorless prisms, mp 273-275° C. (decomp.).

Working Example 66

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(2-naphthyl)-oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-naphthyl)oxazole. Theyield was 77%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 131-132° C.

Working Example 67

In substantially the same manner as in Working Example 48,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(2-benzo[b]thienyl)-4-chloromethyloxazole to give2-(2-benzo[b]thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 68%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 149-150° C.

Working Example 68

In substantially the same manner as in Working Example 47,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with ethyl4-chloromethyl-2-oxazole-propionate to give ethyl4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolepropionate as anoily product. The yield was 70%.

NMR(δ ppm in CDCl₃): 1.25(3H,t,J=7 Hz), 2.0-2.2(2H,m), 2.56(2H,t,J=7.5Hz), 2.82(2H,t,J=7 Hz), 3.11(2H,t,J=7 Hz), 3.92(2H,t,J=7 Hz),4.16(2H,q,J=7 Hz), 4.94(2H,s), 6.85-6.95(3H,m), 7.0-7.1(3H,m),7.46(1H,s), 7.59(1H,s)

Working Example 69

In substantially the same manner as in Working Example 47,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(2,2-diphenyl ethenyl)oxazole to give2-(2,2-diphenylethenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazoleas an oily product. The yield was 88%.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.56(2H,t,J=7.5 Hz), 3.92(2H,t,J=7Hz), 4.95(2H,s), 6.85-7.0(4H,m), 7.0-7.1(3H,m), 7.2-7.5(10H,m)

Working Example 70

In substantially the same manner as in Working Example 60, ethyl4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolepropionate wassubjected to reduction to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolepropanol. The yieldwas 80%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 63-64° C.

Working Example 71

In substantially the same manner as in Working Example 62,2-(2,2-diphenylethenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolewas subjected to catalytic hydrogenation to give2-(2,2-diphenylethyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 82%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 79-80° C.

Working Example 72

Sodium hydride (90 mg) was added to a solution of1-[3-(4-hydroxyphenyl)propyl]imidazole (405 mg) in N,N-dimethylformamide at room temperature and stirred for 1.5 hours.4-Chloromethyl-2-(2-thienyl)oxazole (480 mg) was added, and theresultant was stirred at 90° C. for further 2 hours. The reactionmixture was poured into water, and extracted with ethyl acetate. Theethyl acetate layer was washed with water, dried (MgSO₄), andconcentrated under reduced pressure. The residue was subjected to asilica gel chromatography. From the fraction eluted with ethylacetate-methanol (50:1, v/v),4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole (650mg, 89%) was obtained. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 84-85° C.

Working Example 73

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(1-propenyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenozymethyl]-2-(1-propenyl)oxazole. Theyield was 31%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 61-62° C.

Working Example 74

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-[(E)-2-cyclohexylethenyl]oxazole to give2-[(E)-2-cyclohexylethenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 67%. Recrystallization from isopropylether gave colorlessprisms, mp 62-63° C.

Working Example 75

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(4-benzoylphenyl)-4-chloromethyloxazole to give2-(4-benzoylphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 78%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 112-113° C.

Working Example 76

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(2-benzofuranyl)-4-chloromethyl oxazole to give2-(2-benzofuranyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 85%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 122-123° C.

Working Example 77

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(9-fluorenone-2-yl)oxazole to give2-(9-fluorenone-2-yl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 86%. Recrystallization from ethanol gave yellow needles,mp 153-154° C.

Working Example 78

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(9-fluorenylidene)methyloxazole to give2-(9-fluorenylidenemethyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 84%. Recrystallization from ethyl acetate gave yellowprisms, mp 116-117° C.

Working Example 79

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-chloromethyl-5-phenylbenzoxazole to give2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-phenylbenzoxazole. Theyield was 77%. Recrystallization from ethyl acetate-hexane gave paleyellow plates, mp 123-124° C.

Working Example 80

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with5-chloromethyl-2-(2-thienyl)benzoxazole to give5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. Theyield was 81%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 130-131° C.

Working Example 81

In substantially the same manner as in Working Example 72,1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(2-thienyl)oxazole to give4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole, oilysubstance. The yield was 78%.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.60(2H,t,J=7.4 Hz), 3.92(2H,t,J=7Hz), 5.04(2H,d,J=0.8 Hz), 6.75-6.9(4H,m), 7.05-7.3(3H,m), 7.4-7.5(2H,m),7.65-7.7(2H,m).

This oily substance was dissolved in methanol (1 ml), to which4N-hydrochloric acid-ethyl acetate was added, and stirred for 10minutes. The reaction mixture was concentrated, and crystallized fromdiethyl ether. Recrystallization from ethyl acetate gave colorlessprisms, mp 112-113° C.

Working Example 82

In substantially the same manner as in Working Example 72,1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to give4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole.The yield was 71%. Oily substance.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.54(3H,d,J=0.8 Hz), 2.60(2H,t,J=7.5Hz), 3.93(2H,t,J=7 Hz), 5.03(2H,d,J=0.7 Hz), 6.75-6.95(5H,m), 7.07(1H,brs), 7.15-7.25(1H,m), 7.45-7.65(2H,m), 7.63(1H,t,J=0.7 Hz).

Working Example 83

In substantially the same manner as in Working Example 72,1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with2-(4-benzoylphenyl)-4-chloromethyloxazole to gave2-(4-benzoylphenyl)-4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 85%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 97-98° C.

Working Example 84

In substantially the same manner as in Working Example 72,1-[3-(3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give2-(4-benzyloxyphenyl)-4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 81%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 144-145° C.

Working Example 85

In substantially the same manner as in Working Example 72,1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole to give4-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 70%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 75-76° C.

Working Example 86

In substantially the same manner as in Working Example 72,1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give2-(4-benzyloxyphenyl)-4-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole.The yield was 78%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 87-88° C.

Working Example 87

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-phenyloxazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-phenyloxazole. The yieldwas 89%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 113-114° C.

Working Example 88

In substantially the same manner as in Working Example 72,1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-phenyloxazole to give4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenyloxazole. The yieldwas 78%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 62-63° C.

Working Example 89

In substantially the same manner as in Working Example 72,1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with5-chloromethyl-2-(2-thienyl)benzoxazole to give5-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)benzoxazole.The yield was 76%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 86-87° C.

Working Example 90

In substantially the same manner as in Working Example 72,1-[4-(3-hydroxyphenyl)butyl]imidazole was allowed to react with5-chloromethyl-2-(2-thienyl)benzoxazole to give5-[3-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. Theyield was 70%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 97-98° C.

Working Example 91

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-phenylthiazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylthiazole. The yieldwas 78%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 110-111° C.

Working Example 92

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-phenylthiazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-phenylthiazole. The yieldwas 91%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 93-94° C.

Working Example 93

In substantially the same manner as in Working Example 72,1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-phenylthiazole to give4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylthiazole. The yieldwas 81%. Recrystallization from ethyl acetate-hexane gave colorlessprisms, mp 63-64° C.

Working Example 94

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(2-thienyl)thiazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)thiazole. Theyield was 79%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 76-77° C.

Working Example 95

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3-methyl-2-thienyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-methyl-2-thienyl)oxazole.The yield was 78%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 72-73° C.

Working Example 96

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-(3-methyl-2-thienyl)oxazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(3-methyl-2-thienyl)oxazole.The yield was 87%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 88-89° C.

Working Example 97

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(5-ethyl-2-thienyl)oxazole to give2-(5-ethyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 55%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 57-58° C.

Working Example 98

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(4,5,6,7-tetrahydro-2-benzothienyl)oxazole.The yield was 70%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 83-84° C.

Working Example 99

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole to give2-(5-bromo-4-methyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 77%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 92-93° C.

Working Example 100

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole to give2-(5-bromo-4-methyl-2-thienyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole.The yield was 93%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 85-86° C.

Working Example 101

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-5-methyl-2-(2-thienyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyl-2-(2-thienyl)oxazole.The yield was 84%. Recrystallization from acetone-isopropyl ether gavecolorless prisms, mp 102-103° C.

Working Example 102

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-5-methyl-2-(2-thienyl)oxazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-5-methyl-2-(2-thienyl)oxazole.The yield was 81%. Recrystallization from acetone-isopropyl ether gavecolorless prisms, mp 85-86° C.

Working Example 103

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(2-furyl)-5-methyloxazole to give2-(2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyloxazole.The yield was 79%. Recrystallization from acetone-isopropyl ether gavecolorless prisms, mp 89-90° C.

Working Example 104

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-[(E)-2-(2-thienyl)ethenyl]oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-(2-thienyl)ethenyl]oxazole.The yield was 92%. Recrystallization from ethyl acetate-isopropyl ethergave colorless prisms, mp 131-132° C.

Working Example 105

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-[(E)-2-(2-furyl)ethenyl]oxazole to give2-[(E)-2-(2-furyl)ethenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 70%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 122-123° C.

Working Example 106

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(5-chloro-2-furyl)-4-chloromethyloxazole to give2-(5-chloro-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 86%. Recrystallization from ethyl acetate-isopropyl ethergave colorless prisms, mp 88-89° C.

Working Example 107

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-(5-bromo-2-furyl)-4-chloromethyloxazole to give2-(5-bromo-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 87%. Recrystallization from ethyl acetate-isopropyl ethergave colorless needles, mp 115-116° C.

Working Example 108

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(5-methyl-2-furyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-furyl)oxazole.The yield was 94%. Recrystallization from ethyl acetate-isopropyl ethergave colorless prisms, mp 109-110° C.

Working Example 109

A mixture of 1-[3-(4-hydroxyphenyl)propyl]imidazole (465 mg),4-chloromethyl-2-(5-methyl-2-thienyl)oxazole (600 mg), potassiumcarbonate (315 mg) and N,N-dimethylformamide (15 ml) was stirred at 80°C. for 14 hours. The reaction mixture was poured into water, andextracted with ethyl acetate. The ethyl acetate layer was washed withwater, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with ethyl acetate-methanol (20:1, v/v), crystals of4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole(490 mg, 56%) was obtained. Recrystallization from ethyl acetate-hexanegave colorless prisms, mp 83-84° C.

Working Example 110

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(5-chloro-2-thienyl)oxazole to give2-(5-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 68%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 77-78° C.

Working Example 111

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3-thienyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-thienyl)oxazole. Theyield was 65%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 102-103° C.

Working Example 112

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(2-furyl)oxazole to give2-(2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. Theyield was 31%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 92-93° C.

Working Example 113

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-chloromethylbenzoxazole to give2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]benzoxazole. The yield was28%. Recrystallization from ethyl acetate-hexane gave pale brown prisms,mp 81-82° C.

Working Example 114

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with5-chloromethyl-2-(2-thienyl)benzoxazole to give5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)benzoxazole.The yield was 53%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 130-131° C.

Working Example 115

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with5-(4-chloromethyl-2-oxazolyl)-2-phenylbenzoxazole to give5-[4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolyl]-2-phenylbenzoxazole.The yield was 53%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 166-167° C.

Working Example 116

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(5-phenyl-2-benzothienyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-phenyl-2-benzothienyl)oxazole.The yield was 67%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 168-169° C.

Working Example 117

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with5-chloromethyl-2-phenylbezoxazole to give5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylbenzoxazole. Theyield was 67%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 137-138° C.

Working Example 118

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with2-benzyloxy-5-chloromethylpyridine to give2-benzyloxy-5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]pyridine. Theyield was 65%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 84-85° C.

Working Example 119

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with3-chloromethyl-7-phenylquinoline to give3-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-7-phenylquinoline. The yieldwas 59%. Recrystallization from ethanol gave colorless prisms, mp135-136° C.

Working Example 120

In substantially the same manner as in Working Example 109,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with6-bromo-2-chloromethylimidazo[1,2-a]pyridine to give6-bromo-2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]imidazo[1,2-a]pyridine.The yield was 57%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 103-104° C.

Working Example 121

In substantially the same manner as in Working Example 109,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-(2-thienyl)oxazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)oxazole. Theyield was 61%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 106-107° C.

Working Example 122

In substantially the same manner as in Working Example 109,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole.The yield was 65%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 82-83° C.

Working Example 123

In substantially the same manner as in Working Example 109,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with2-(4-benzoylphenyl)-4-chloromethyloxazole to give2-(4-benzoylphenyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole.The yield was 64%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 91-92° C.

Working Example 124

In substantially the same manner as in Working Example 109,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with2-(4-benzyloxyphenyl)-4-chloromethyloxazole to give2-(4-benzyloxyphenyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole.The yield was 54%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 118-120° C.

Working Example 125

Sodium hydride (oily, 60%, 660 mg) was added to a solution of2-[(E)-2-phenylethenyl]-4-oxazolylmethanol (3.02 g) inN,N-dimethylformamide (30 ml) and stirred at 90° C. for 30 minutes, towhich was added a solution of2-chloro-5-[3-(1-imidazolyl)propyl]pyridine (1.10 g) inN,N-dimethylformamide (10 ml). The resultant was stirred at 90° C. for14 hours. The reaction mixture was poured into water, and extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium bicarbonate and brine, dried (MgSO₄), and concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with ethylacetate-hexane-methanol (10:1:0.5, v/v), crystals of5-[3-(1-imidazolyl)propyl]-2-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]pyridine(900 mg, 47%) was obtained. Recrystallization ethyl acetate-hexane gavepale brown prisms, mp 120-121° C.

Working Example 126

In substantially the same manner as in Working Example 125,2-(2-thienyl)-4-oxazolylmethanol was allowed to react with2-chloro-5-[3-(1-imidazolyl)propyl]pyridine to give5-[3-(1-imidazolyl)propyl]-2-[2-(2-thienyl)-4-oxazolylmethoxy]pyridine.The yield was 67%. Recrystallization from ethyl acetate-hexane gavebrown prisms, mp 86-87° C.

Working Example 127

In substantially the same manner as in Working Example 8,3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propylmathanesulfonate was allowed to react with imidazole to give4-[4-[3-(1-imidazolyl)propyl]phenylthiomethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 70%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 74-75° C.

Working Example 128

In substantially the same manner as in Working Example 62,2-(9-fluorenylidenemethyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolewas subjected to catalytic hydrogenation to give2-(9-fluorenylmethyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 72%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 145-146° C.

Working Example 129

To a solution4-[4-[3-(1-imidazolyl)propyl]phenylthiomethyl]-2-[(E)-2-phenylethenyl]oxazole(500 mg) in dichloromethane (10 ml) was added to m-chloroperbenzoic acid(260 mg) at 0° C. and stirred for one hour. The reaction mixture waswashed with aqueous sodium sulfite, saturated aqueous sodium bicarbonateand water in this order, dried (MgSO₄), and concentrated under reducedpressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with ethyl acetate-methanol(20:1, v/v), crystals of4-[4-[3-(1-imidazolyl)propyl]phenylsulfonylmethyl]-2-[(E)-2-phenylethenyl]oxazole(380 mg, 73%) was obtained. Recrystallization from ethyl acetate-hexanegave colorless prisms, mp 116-117° C.

Working Example 130

In substantially the same manner as in Working Example 129,4-[4-[3-(1-imidazolyl)propyl]phenylthiomethyl]-2-[(E)-2-phenylethenyl]oxazole(500 mg) was oxidized by use of m-chloroperbenzoic acid (540 mg) to give4-[4-[3-(1-imidazolyl)propyl]phenylsulfonylmethyl]-2-[(E)-2-phenylethenyl]oxazole.The yield was 72%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 140-141° C.

Working Example 131

A mixture of2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole(300 mg), 2-chloromethylpyridine.hydrochloric acid (260 mg), potassiumcarbonate (330 mg) and N,N-dimethylformamide (10 ml) was stirred at 110°C. for 8 hours. The reaction mixture was poured into water, andextracted with ethyl acetate. The ethyl acetate-hexane was washed withwater, dried (MgSO₄), and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography. From thefraction eluted with chloroform-methanol (50:1, v/v), crystals of4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[4-(2-pyridylmethoxy)phenyl]oxazole(95 mg, 26%). Recrystallization from ethyl acetate-hexane gavecolorless, mp 119-120° C.

Working Example 132

To a solution of2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole(250 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride(oily, 60%, 30 mg) and stirred at room temperature for one hour, towhich chlorodiphenylmethane (270 mg) was added and stirred at 80° C. for6 hours. The reaction mixture was poured into water, and extracted withethyl acetate. The ethyl acetate layer was washed with 1N-sodiumhydroxide and water, dried (MgSO₄), and concentrated under reducedpressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with ethyl acetate-methanol(50:1, v/v), crystals of2-(4-diphenylmethoxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole(155 mg, 43%) was obtained. Recrystallization from ethyl acetate-hexanegave colorless prisms, mp 106-107° C.

Working Example 133

In substantially the same manner as in Working Example 131,2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolewas allowed to react with 4-chlorobenzylchloride to give2-[4-(4-chlorobenzyloxy)phenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 30%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 151-152° C.

Working Example 134

In substantially the same manner as in Working Example 131,2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolewas allowed to react with piperonylchloride to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[4-(3,4-methylenedioxyphenylmethoxy)phenyl]oxazole.The yield was 43%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 124-125° C.

Working Example 135

To a mixture of2-(5-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolel(600 mg), 2N-sodium carbonate (2.4 ml),tetrakis(triphenylphosphine)palladium (105 mg) and toluene (12 ml) wasadded dropwise aqueous phenylboronic acid (245 mg) in ethanol (3 ml)under argon-stream at room temperature and stirred at 90° C. for 15hours. To the reaction mixture was added ethyl acetate, washed with2N-sodium hydroxide and water, dried (MgSO₄), and concentrated underreduced pressure. The residue was subjected to a silica gel columnchromatography. From the fraction eluted with chloroform-methanol (50:1,v/v), crystals of4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-phenyl-2-thienyl)oxazole(430 mg, 54%) was obtained. Recrystallization from ethyl acetate-hexanegave pale yellow prisms, mp 128-129° C.

Working Example 136

In substantially the same manner as in Working Example 135,6-bromo-2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]imidazo[1,2-a]pyridinewas allowed to react with phenylboronic acid to give2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-6-phenylimidazo[1,2-a]pyridine.The yield was 78%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 106-107° C.

Working Example 137

In substantially the same manner as in Working Example 135,2-(5-bromo-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolewas allowed to react with phenylboronic acid to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-phenyl-2-furyl)oxazole.The yield was 92%. Recrystallization from ethyl acetate-isopropyl ethergave colorless needles, mp 130-131° C.

Working Example 138

A mixture of2-(5-bromo-4-methyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole(700 mg), zinc powder (200 mg), acetic acid (5 ml) and water (5 ml) washeated for 4 hours under reflux. The residue was filtered off, thefiltrate was concentrated. To the residue was added ethyl acetate,washed with saturated aqueous sodium bicarbonate and water, dried(MgSO₄), and concentrated under reduced pressure to give crystals of4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(4-methyl-2-thienyl)oxazole(470 mg, 81%). Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 077-178° C.

Working Example 139

In substantially the same manner as in Working Example 138,2-(5-bromo-4-methyl-2-thienyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazolewas reduced by zinc powder to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(4-methyl-2-thienyl)oxazole.The yield was 89%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 77-78° C.

Working Example 140

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3-chloro-2-thienyl)oxazole to give2-(3-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 77%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 69-70° C.

Working Example 141

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(4-chloro-2-thienyl)oxazole to give2-(4-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 80%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 69-70° C.

Working Example 142

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(5-methoxy-2-thienyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methoxy-2-thienyl)oxazole.The yield was 74%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 96-97° C.

Working Example 143

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with4-chloromethyl-2-(3-furyl)oxazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-furyl)oxazole. Theyield was 93%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 85-87° C.

Working Example 144

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with4-chloromethyl-2-(5-methyl-2-furyl)oxazole to give4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-furyl)oxazole.The yield was 99%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 91-92° C.

Working Example 145

Sodium hydride (oily, 60%, 120 mg) was added to ethanol (15 ml) at 0° C.and stirred at room temperature for one hour, to which1-[3-(4-hydroxyphenyl)propyl]imidazole (506 mg) was added, and stirredat room temperature for further one hour.4-chloromethyl-2-(2-thienylmethyl)oxazole (580 mg) was added and heatedfor 4 hours under reflux. The reaction mixture was concentrated, towhich water was added, and extracted with ethyl acetate. The ethylacetate layer was washed with 2N-sodium hydroxide and brine, dried(MgSO₄), and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography. From the fractioneluted with ethyl acetate-methanol (95:5, v/v),4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienylmethyl)oxazole.The yield was 93%. Oily substance.

NMR(δ ppm in CDCl₃): 2.0-2.2(2H,m), 2.56(2H,t,J=7.4 Hz), 3.92(2H,t,J=7.2Hz), 4.33(2H,s), 4.96(2H,s), 6.85-7.0(5H,m), 7.0-7.1(3H,m),7.15-7.25(1H,m), 7.45(1H,s), 7.61(1H,s).

Working Example 146

To a mixture of 2-(1-pyrrolyl)-4-thiazolylmethanol (0.45 g),triethylamine (0.42 ml) and ethyl acetate (20 ml) was added dripwisemethanesulfonyl chloride (0.23 ml) at 0° C., and then stirred for onehour. To the reaction mixture was added water, and the ethyl acetatelayer was separated, washed with water, dried (MgSO₄), and concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran (5ml), which was added to a solution prepared by adding sodium hydride(oily, 60%, 92 mg) to a solution of1-[3-(4-hydroxyphenyl)propyl]imidazole (420 mg) in N,N-dimethylformamide(10 ml). After stirring for 2 hours, the reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate layer waswashed with 2N-aqueous sodium hydroxide and then water, dried (MgSO₄),and concentrated under reduced pressure. The residue was subjected to asilica gel column chromatography. From the fraction eluted with ethylacetate-methanol (95:5, v/v), crystals were obtained. Recrystallizationfrom ethyl acetate-hexane gave4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(1-pyrrolyl)thiazole (530mg, 70%), colorless prisms, mp 93-94° C.

Working Example 147

In substantially the same manner as in Working Example 146,2-(3-pyridyl)-4-thiazolylmethanol was mesylated, which was allowed toreact with 1-[3-(4-hydroxyphenyl)propyl]imidazole to give4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(3-pyridyl)thiazole. Theyield was 35%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 67-68° C.

Working Example 148

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with4-chlorometyl-2-(5-cyano-2-thienyl)oxazole to obtain2-(5-cyano-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole.The yield was 70%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 73-74° C.

Working Example 149

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole was reacted with4-chloromethyl-2-(2-thienyl)oxazole to obtain4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-(2-thienyl)oxazole.The yield was 80%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 94-95° C.

Working Example 150

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole was reacted with4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to obtain4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-(5-methyl-2-thienyl)oxazole.The yield was 72%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 92-93° C.

Working Example 151

In substantially the same manner as in Working Example 72,1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole was reacted with4-chloromethyl-2-(2-thienyl)oxazole to obtain4-[2-chloro-4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole.The yield was 77%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 93-94° C.

Working Example 152

In substantially the same manner as in Working Example 72,1-[3-(3-chloro-4-hydroxyphenyl)propyl]imidazole was reacted with4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to obtain4-[2-chloro-4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole.The yield was 83%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 95-96° C.

Working Example 153

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with4-chloromethyl-2-(2-thienyl)thiazole to obtain4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)thiazole. Theyield was 82%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 108-109° C.

Working Example 154

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with3-chloromethyl-7-(2-thienyl)quinoline to obtain3-[4-[3-(1-imidazolyl)propyl]phonexymethyl]-7-(2-thienyl)quinoline. Theyield was 82%. Recrystallization from ethanol gave colorless prisms, mp157-158° C.

Working Example 155

Diethyl azodicarboxylate (1.20 g) was added dropwise to a stirredmixture of 2-(2-thienyl-4-oxazolyl)ethanol (700 mg).1-[3-(4-hydroxyphenyl)propyl]imidazole (670 mg), triphenylphosphine(1.73 g), and tetrahydrofuran (50 ml) at room temperature. Afterrefluxing for 3 h, the reaction mixture was concentrated. The residuewas purified by silica gel column chromatography. From the fractioneluted with ethyl acetate-methanol (100:1, v/v)4-[2-[4-[3-(1-imidazolyl)propyl]phenoxy]ethyl]-2-(2-thienyl)oxazole (690mg, 55%) was obtained. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 77-78° C.

Working Example 156

In substantially the same manner as in Working Example 146,3-[2-(2-thienyl)-4-oxazolyl]propanol was mesylated and then reacted with1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain4-[3-[4-[3-(1-imidazolyl)propyl]phenoxy]propyl]-2-(2-thienyl)oxazole.The yield was 72%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 99-100° C.

Working Example 157

In substantially the same manner as in Working Example 146,4-(2-thienyl)-2-thiazolylmethanol was mesylated and then reacted with1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-4-(2-thienyl)oxazole. Theyield was 84%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 123-124° C.

Working Example 158

In substantially the same manner as in Working Example 146,5-(2-thienyl)-2-thiazolylmethanol was mesylated and then reacted with1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-(2-thienyl)thiazole. Theyield was 66%. Recrystallization from ethyl acetate-hexane gave orangeprisms, mp 82-84° C.

Working Example 159

2-(2-thienyl)-5-thiazolylmethanol (395 mg) was dissolved in thionylchloride (3 ml) at 0° C. After stirring for 15 min. the reaction mixturewas concentrated. The residue was dissolved in ethyl acetate and washedwith saturated aqueous sodium bicarbonate and water. The ethyl acetatelayer was separated, dried (MgSO₄), and concentrated. The residue wasdissolved in tetrahydrofuran (5 ml) and then added to a stirred solutionprepared from 60% sodium hydride in oil (76 mg),1-[3-(4-hydroxyphenyl)propyl]imidazole (344 mg) andN,N-dimethylformamide (10 ml). After stirring for 2 h, the reactionmixture was poured into water and extracted with ethyl acetate. Theethyl acetate layer was washed with 2N sodium hydroxide solution andwater, dried (MgSO₄), and concentrated to obtain5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)thiazole (567mg, 87%). Recrystallization from ethyl acetate-hexane gave pale yellowprisms, mp 112-113° C.

Working Example 160

In substantially the same manner as in Working Example 159,2-(2-thienyl)-5-thiazolylmethanol was chlorinated and then reacted with1-[4-(4-hydroxyphenyl)butyl]imidazole to obtain5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(2-thienyl)thiazole. Theyield was 86%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 128-129° C.

Working Example 161

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with4-chloromethyl-2-(5-methyl-2-thienyl)thiazole to obtain4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)thiazole.The yield was 88%. Recrystallization from ethyl acetate-hexane gavecolorless needles, mp 78-79° C.

Working Example 162

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with4-chloromethyl-2-(5-methyl-2-thienyl)thiazole to obtain4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-thienyl)thiazole.The yield was 74%. Recrystallization from ethyl acetate-hexane gave paleyellow needles, mp 81-82° C.

Working Example 163

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with2-chloromethyl-5-(2-thienyl)oxazole to obtain2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-(2-thienyl)oxazole. Theyield was 90%. Recrystallization from ethyl acetate-hexane gavecolorless prisms, mp 75-76° C.

Working Example 164

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with2-chloormethyl-5-(2-thienyl)oxazole to obtain2-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-5-(2-thienyl)oxazole. Theyield was 98%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 136-138° C.

Working Example 165

A solution of4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-(2-thienyl)ethenyl]oxazole(200 mg) in methanol (10 ml)-tetrahydrofuran (4 ml) was hydrogenated onpalladium carbon (10%, wet, 70 mg) at 4 atm. After removal of thecatalyst by filtration, the filtrate was concentrated. The hydrogenationwas repeated three times to obtain4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[2-(2-thienyl)ethyl]oxazole.Recrystallization from ethyl acetate-methanol gave colorless prisms (155mg, 79%), mp 68-70° C.

Working Example 166

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with5-chloromethyl-3-phenyl-1,2,4-oxadiazole to obtain5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-3-phenyl-1,2,4-oxadiazole.The yield was 51%. Recrystallization from ethyl acetate-hexane gavecolorless needles, mp 124-125° C.

Working Example 167

In substantially the same manner as in Working Example 72,1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole to obtain5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-3-(2-thienyl)-1,2,4-oxadiazole.The yield was 41%. Recrystallization from ethyl acetate-hexane gave paleyellow prisms, mp 118-119° C.

Working Example 168

In substantially the same manner as in Working Example 72,1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole to obtain5-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-3-(2-thienyl)-1,2,4-oxadiazole.The yield was 29%. Recrystallization from a ethyl acetate-MeOH gavecolorless prisms, mp 94-95° C.

INDUSTRIAL APPLICABILITY

The present invention provides the compounds having excellent actions ofinhibiting tyrosine kinase and provides the antitumor agents, with lessadverse side effects, based on novel action mechanism.

The compound (I) of this invention or salts thereof have tyrosine kinaseinhibiting activity, which can be used for prophylaxis or therapy oftyrosine kinase dependent diseases in mammals. These tyrosine kinasedependent diseases include diseases stimulating cell proliferation dueto abnormal tyrosine kinase activity. In other words, the compound (I)or salts thereof can be safely used as prophylaxis or therapy ofdiseases caused by abnormal cell proliferation including, among others,breast cancer, prostate cancer, pancreactic cancer, gastric cancer, oratherosclerosis, angiogenesis (solid tumor or sarcoma accompanied withangiogenesis, metastatis of tumors accompanied with angiogenesis, anddiabetic retinopathy accompanied with angiogenesis), viral diseases(e.g. HIV infection).

Tyrosine kinase dependent diseases further include cardiovasculardisease associated with abnormal tyrosine kinase activities. Therefore,the compound (I) of this invention or salts thereof can be used also forprophylaxis or therapy of cardiovascular diseases such as restenosis.

The compound (I) of this invention or salts thereof are useful asantitumor agents such as therapeutic agents, especially, breast cancer,prostate cancer, pancreatic cancer and gastric cancer.

What is claimed is:
 1. A heterocyclic compound represented by theformula:

wherein R stands for an aromatic heterocyclic group which may beoptionally substituted, X stands for an oxygen atom, an optionallyoxidized sulfur atom, —C(═O)— or —CH(OH)—, Y stands for CH or N m standsfor an integer of 1 to 10, n stands for an integer of 1 to 5, the cyclicgroup

 stands for an aromatic azole group which may be substituted, and thering A may be further substituted, or a salt thereof.
 2. The compoundaccording to claim 1, wherein the cyclic group;

is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl orbenzimidazolyl, or they may be substituted with one or two groupsselected from (i) alkyl, (ii) aryl, (iii) hydroxyalkyl, (iv) carboxyl,(v) alkoxycarbonyl and (vi) carbamoyl.
 3. The compound according toclaim 1, wherein m is an integer of 3 to
 5. 4. The compound according toclaim 1, wherein n is
 1. 5. The compound according to claim 2, wherein Xis oxygen atom.
 6. The compound according to claim 1, wherein R is anoptionally substituted oxazolyl or an optionally substituted thiazolyl.7. The compound according to claim 1, wherein R is oxazolyl,benzoxazolyl or thiazolyl, or they may be substituted with one or twogroups selected from, (i) aryl which may be substituted with one or twogroups selected from hydroxyl, alkoxy, arylalkoxy, alkyl, cyano, halogenatom and tetrazolyl, (ii) alkyl, (iii) hydroxyalkyl, (iv)alkoxycarbonylalkyl, (v) alkyl substituted with one or two aryl groups,(vi) alkenyl substituted with one or two aryl groups, (vii) cycloalkyl,(viii) a partially saturated naphthyl, (ix) thienyl or furyl, or theymay be substituted with one or two groups selected from hydroxy, alkoxy,arylalkoxy group, alkyl, cyano, aryl and hydrogen atom, (x) benzofuranyland (xi) benzothienyl.
 8. The compound according to claim 1, wherein Ris oxazolyl, benzoxazolyl or thiazolyl, or they may be substituted withone or two groups selected from (i) aryl which may be substituted withone or two groups selected from hydroxyl, alkoxy, arylalkoxy, alkyl,cyano, halogen atom and tetrazolyl, (ii) alkyl, (iii) hydroxyalkyl, (iv)alkoxycarbonylalkyl, (v) alkyl substituted with one or two aryl groups,(vi) alkenylsubstituted with one or two aryl groups, (vii) cycloalkyl,(viii) a partially saturated naphthyl, (ix) thienyl or furyl, or theymay be substituted with one or two groups selected from hydoxy, alkoxy,arylalkoxy, alkyl, cyano, aryl and hydrogen atom, (x) benzofuranyl and(xi) benzothienyl, X is oxygen atom, m is an integer of 0 to 6, n is 1,the cyclic group;

 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazoryl orbenzimidazolyl, or they may be substituted with one or two groupsselected from (i) alkyl, (ii) aryl, (iii) hydroxyalkyl, (iv) carboxyl,(v) alkoxycarbonyl and (vi) carbamoyl.
 9. The compound according toclaim 1, wherein R is oxazolyl substituted with arylalkenyl orarylalkoxyaryl, X is oxygen atom, m is 3 or 4, n is 1, the cyclic group;

 is imidazolyl or triazolyl, the ring A is 1,3-phenylene or1,4-phenylene.
 10. The compound according to claim 1, wherein R isoxazolyl or thiazolyl substituted with thienyl, X is oxygen atom, m is 3or 4, n is 1 and the cyclic group;

 is imidazolyl or triazolyl.
 11. The compound according to claim 1,wherein R is benzoxazolyl substituted with thienyl, X is oxygen atom, mis 3 or 4, n is 1, the cyclic group;

 is imidazolyl or triazolyl, the ring A is 1,3-phenylene or1,4-phenylene.
 12. The compound according to claim 1, which is1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl-1,2,4-triazoleor a salt thereof,4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazoleor a salt thereof,4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazoleor a salt thereof,4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazoleor a salt thereof,2-(4-benzyloxyphenyl)-4-[4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazolea salt thereof,4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole or asalt thereof,4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazoleor a salt thereof,2-(5-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazoleor a salt thereof,4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)thiazole or asalt thereof, or5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)benzoxazole ora salt thereof.
 13. A pharmaceutical composition which comprises acompound as claimed in claim 1 and a pharmaceutically acceptablecarrier.
 14. The pharmaceutical composition according to claim 13, whichis a composition for antitumor.
 15. The pharmaceutical compositionaccording to claim 14, which is a composition for prophylaxis ortreatment of breast cancer or prostate cancer.
 16. A tyrosine kinaseinhibitor comprising a compound or a salt thereof as claimed in claim 1and a pharmaceutically acceptable carrier.
 17. A method for preparationof a medicinal agent for prophylaxis or treatment of cancer comprisingadmixing a compound as claimed in claim 1 with a pharmaceuticallyacceptable carrier.
 18. A method which comprises administering aneffective amount of a compound as claimed in claim 1 in apharmaceutically acceptable carrier to provide a prophylactic ortherapeutic action for cancer in warm blooded animals.
 19. A method forproducing a compound represented by the formula:

wherein R stands for an aromatic heterocyclic group which may beoptionally substituted, X stands for oxygen atom, an optionally oxidizedsulfur atom, —C(═O)— or —CH(OH), Y stands for CH or N, m stands for aninteger of 1 to 10, n stands for an integer of 1 to 5, the cyclic group;

 stands for an aromatic azole group which may be substituted, and thering A may be further substituted, or a salt thereof, which comprisesreacting a compound represented by the formula:

wherein W stands for a leaving group and other symbols are the same asabove, or a salt thereof, with a compound represented by the formula:

wherein the cyclic group;

stands for an aromatic azole group which may be substituted, or a saltthereof.
 20. The compound according to claim 1, wherein X is oxygenatom, an optionally oxidized sulfur atom or —CH(OH).
 21. The compoundaccording to claim 1, wherein the cyclic group

is a 5-membered aromatic monocyclic heterocyclic group containing, asthe ring forming atoms besides the carbon atoms, 1 to 4 nitrogen atomsand optionally containing one oxygen atom or one sulfur atom, which maybe substituted.